UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) UvA-DARE (Digital Academic Repository) Lung-protective perioperative mechanical ventilation Hemmes, S.N.T. Publication date 2015 Document Version Final published version Link to publication Citation for published version (APA): Hemmes, S. N. T. (2015). Lung-protective perioperative mechanical ventilation. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date:01 Jun 2022
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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
Publication date2015Document VersionFinal published version
Link to publication
Citation for published version (APA):Hemmes, S. N. T. (2015). Lung-protective perioperative mechanical ventilation.
General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).
Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.
Beyond the dangers of high tidals, on the perils of PEEP
Sabrine N.T. Hemmes
COLOFONLung-protective perioperative mechanical ventilationAcademic thesis, University of Amsterdam, Amsterdam, The Netherlands
ISBN: 978-94-6233-149-5
Author: Sabrine N.T. HemmesLay-out: Barbara ten Brink Cover: Image by Heng Swee Lim - Website: http://www.ilovedoodle.comPrint: Gildeprint, Enschede, The Netherlands
ten overstaan van een door het College voor Promoties ingestelde commissie,
in het openbaar te verdedigen in de Aula der Universiteit
op vrijdag 11 december 2015, te 13.00 uur
door Sabrine Nienke Tallechina Hemmes
geboren te Hilversum
PROMOTIECOMMISSIE
Promotores: prof. dr. M.J. Schultz Universiteit van Amsterdam prof. dr. dr. M.W. Hollmann Universiteit van Amsterdam
Overige leden: prof. dr. L.P.H.J. Aarts Universiteit van Leiden prof. dr. C. Boer Vrije Universiteit Amsterdam prof. dr. M.A. Boermeester Universiteit van Amsterdam prof. dr. G. Cinnella University of Foggia, Italy prof. dr. M.M. Levi Universiteit van Amsterdam prof. dr. W.S. Schlack Universiteit van Amsterdam prof. dr. M.B. Vroom Universiteit van Amsterdam
Faculteit der Geneeskunde
CONTENTS
Chapter 1 General introduction and outline of the thesis
Chapter 2 Intraoperative ventilatory strategies to prevent postoperative pulmonary complications – a metaanalysis
Current Opinion in Anesthesiology 2013
Chapter 3 Intraoperative protective mechanical ventilation for prevention of postoperative pulmonary complications – a comprehensive review of the role of tidal volume, positive end-expiratory pressure and lung recruitment manoeuvres
Anesthesiology 2015
Chapter 4 LAS VEGAS – Local assessment of ventilatory management during general anaesthesia for surgery and its effects on postoperative pulmonary complications: a prospective, observational, international, multicentre cohort study
European Journal of Anaesthesiology 2013
Chapter 5 Intraoperative ventilation strategies and patient outcomes following surgery: an international observational study (LAS VEGAS)
Manuscript submitted
Chapter 6 Protective ventilation with lower tidal volumes and high PEEP versus conventional ventilation with high tidal volume and low PEEP in patients under general anaesthesia for surgery: A systematic review and individual patient data metaanalysis
Anesthesiology 2015
Chapter 7 Rationale and study design of PROVHILO - a worldwide multicentre randomized controlled trial on protective ventilation during general anaesthesia for open abdominal surgery
Trials 2011
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Chapter 8 High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial
Lancet 2014
Chapter 9 Positive end-expiratory pressure during surgery - Authors' reply Lancet 2014
Chapter 10 Incidence of mortality and morbidity related to postoperative lung injury in patients who have undergone abdominal or thoracic surgery: a systematic review and metaanalysis
Lancet Respiratory Medicine 2014
Chapter 11 Positive end – expiratory pressure following coronary artery bypass grafting
Minerva Anestesiologica 2012
Chapter 12 Summary and general discussion
Appendices Nederlandse samenvatting
Contributing authors and affiliations
Publications
PhD Portfolio
Curriculum Vitae
Acknowledgements
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Chapter 1
General introduction and outline of the thesis
Hemmes SNT, Schultz MJ
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Prevention of postoperative pulmonary complications
Mechanical ventilation is frequently considered a simple but foremost harmless intervention in patients under general anaesthesia for surgery. Recent investigations, however, suggest that intraoperative ventilation has a strong potential to cause so called ventilator-associated lung injury.1 Of all patients undergoing ventilation during general anaesthesia for surgery, 5% will develop one or more postoperative pulmonary complications, that are associated with high morbidity and mortality.2, 3 There are several mechanisms through which intraoperative ventilation could cause ventilator–associated lung injury, as such contributing to development of postoperative pulmonary complications (fig. 1). First, positive pressure ventilation can overstretch patent alveoli causing damage in those parts of the lung that are aerated during the whole breath cycle (fig. 1A & 1C).4, 5 Second, repeated opening and closing of alveoli that collapse at the end of expiration is associated with increased shear stress, known to cause epithelial destruction (fig. 1B & 1D).6-8 Third, hyperoxia can result in absorption atelectasis, and cause injury of cellular structures through increased production of reactive oxygen species (ROS) (fig. 1E).9 All these harmful effects are suggested to be preventable through the use of lung–protective ventilator settings, using low tidal volumes for prevention of overdistension,10,11 use of positive end–expiratory pressure (PEEP)12, 13 with or without so–called recruitment manoeuvres to prevent repeated opening and closing,14, 15 and low oxygen fractions (FiO2) preventing atelectasis and ROS production.16 These insights have led to a paradigm shift from supranormal intraoperative ventilation, with large tidal volumes to prevent atelectasis and high levels of FiO2 to maximize oxygenation, to safer ventilation, using lower levels of tidal volumes, higher levels of PEEP and lower arterial oxygen thresholds.
Tidal volumes
Low tidal volumes in animal studiesThe harmful effects of high tidal volumes were first recognized in animal studies of ventilation.17 In these preclinical studies lungs of animals were either challenged with injurious ventilation strategies using different tidal volumes alone, or in combination with other challenges such as intratracheal instillation of lipopolysaccharide or live bacteria.18 More or less they all showed that the extent of alveolar damage and pulmonary oedema depends on the size of tidal volumes used.17, 18
Low tidal volumes in patients with ARDSTraditionally patients were ventilated with large tidal volumes of 10 to 15 mL/kg predicted body weight (PBW). These volumes far exceeded the range of normal tidal volumes in healthy subjects in rest (7 to 8 mL/kg PBW). The rationale was to prevent atelectasis, as such optimizing oxygenation and ventilation.19 Randomized controlled clinical trials in critically ill patients with the acute respiratory distress syndrome (ARDS), however, showed large tidal volumes to be harmful.20-24 Two metaanalyses convincingly confirmed that ventilation with low tidal volumes in patients with ARDS is associated with improved survival.25, 26 Consequently, nowadays ventilation with low tidal volumes is standard of care in these patients.27, 28
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Low tidal volumes in critically ill patients without ARDSThe finding that ventilation with low tidal volumes benefits patients with ARDS evoked interest in lung–protective ventilation in critically ill patients who need ventilation for other reasons than ARDS, for example comatose patients with neurologic damage and patients after major cardiac surgery. One randomized controlled trial comparing ventilation with low tidal volumes (6 mL/kg PBW) to ventilation with high tidal volumes (10 mL/kg PBW) indeed suggested benefit from low tidal volumes, as it seemed to reduce the incidence of ARDS.29 These findings were confirmed in a series of metaanalyses.18, 30, 31 In addition, these analyses revealed that ventilation with low tidal volumes was associated with earlier liberation from the ventilator. Even though a substantial reduction in tidal volume size is seen in recent years,27, 28 lung–protective ventilation using low tidal volumes is not yet considered standard of care for critically ill patients who need ventilatory support for reasons other than ARDS.
Low tidal volumes during intraoperative ventilationSeveral small clinical trials of intraoperative ventilation suggested that tidal volume reduction could reduce local production of inflammatory mediators and possibly improve pulmonary mechanics.32-34 A large retrospective trial showed that pressure- and volume–limited ventilation during general surgery decreases the development of postoperative respiratory complications.35 Recently, three randomized controlled trials provided more robust evidence for benefit from this ventilation strategy.36-38 An Italian single–centre trial showed that a ventilation strategy using tidal volumes of 7 mL/kg PBW compared to ventilation with tidal volumes of 9 mL/kg PBW during abdominal surgery was associated with superior postoperative pulmonary function.36 A French multicentre trial found that in patients undergoing abdominal surgery a ventilation strategy with reduced tidal volumes of 6 mL/kg PBW compared to tidal volumes of 12 mL/kg PBW was associated with a decreased incidence of postoperative complications by almost 65%.37 One Chinese trial in patients undergoing spinal fusion reported an even more impressive benefit of tidal volume reduction from 12 to 6 mL/kg PBW on postoperative pulmonary complications.38 Contrasting to these results, one retrospective study showed that use of low tidal volume ventilation (6 to 8 mL/kg PBW) is associated with increased postoperative mortality, though the authors claim this to be caused by insufficient levels of PEEP.39 Despite the suggestion that low tidal volume ventilation in surgery patients is increasingly accepted,40, 41 recent studies show imperfect implementation of this strategy in the operation room.42-45
Positive end–expiratory pressure
Positive end–expiratory pressure in animal studiesSeveral studies in animals with lung injury have shown that ventilation with PEEP compared to ventilation without PEEP improves oxygenation and lung mechanics, and prevents formation of lung edema.5, 17, 46 Similar results came from studies in animals without lung injury. Ventilation with PEEP in combination with low tidal volumes attenuated local production of inflammatory mediators,47-52 lung edema,48, 51 and cell injury.47-52 One important shortcoming of PEEP, however, is that it could cause overdistension of the lung parts that remain aerated during the complete breath cycle.53 In addition, use of higher levels of PEEP could compromise the circulation.54
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Figure 1. Mechanisms through which intraoperative ventilation could cause ventilator–associated lung injuryA) Ventilation at high lung volumes result in overdistention of the lung and hyperinflation may cause gross barotrauma (air leaks), but can also cause an increase in pulmonary oedema; B) ventilation at low lung volumes causes repeated opening and closing of alveoli that collapse at the end of expiration, resulting in increased shear stress and lung injury (atelectrauma). Collapse of large regions of the lung during ventilation at low lung volumes cause lung inhomogeneity; C) ventilation at too high levels of PEEP can aggravate overdistention of lung tissue at end-expiration; D) ventilation at low levels of PEEP increases formation of atelectasis and lung inhomogeneity; E) high levels of fractional inspired oxygen (FiO2) can increase the production of reactive oxygen species (ROS), which have a direct toxic effect on lung cells. Too high levels of FiO2 also increases the risk of resorption atelectasis; F) these mechanical and chemical stressors cause structural and biological changes in the alveoli. Inflammatory mediators are released in the lung and recruit neutrophils. They also cause changes that promote pulmonary fibrosis. The increase in alveolar-capillary permeability causes an increase in pulmonary oedema, but also facilitate translocation of mediators and bacteria to the systemic circulation; G) these structural and biological changes result in lung injury, which can cause an increase in postoperative pulmonary complications and worse clinical outcome with increased length of hospital stay and higher incidence of mortality (H)
Positive end–expiratory pressure in patients with ARDSThree randomized controlled trials in patients with ARDS failed to show an effect of higher levels of PEEP on survival.55-57 One metaanalysis using the individual patient data of these three trials, however, showed survival benefit in patients with more severe ARDS.58 Consequently, nowadays most clinicians use higher levels of PEEP (10 cm H2O and higher) in patients with moderate or severe ARDS.27
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Positive end–expiratory pressure in critically ill patients without ARDSIn critical care patients without ARDS, there is limited evidence for benefit of PEEP.59, 60 One randomized controlled trial in patients at risk for ARDS showed no difference between a strategy using PEEP (5 to 8 cm H2O) and a strategy using a minimal levels of PEEP for adequate oxygenation with regard to later development of ARDS or mortality.59 This was confirmed in another trial in patients without ARDS, but in this trial use of higher levels of PEEP was associated with a lower incidence of ventilator–associated pneumonia.60 In the randomized controlled trial comparing low and high tidal volumes (6 ml/kg PBW versus 10 ml/kg PBW) in patients without ARDS mentioned above,29 an independent association between higher levels of PEEP and development of ARDS was found. In the postoperative phase there is also no clear evidence for benefit from PEEP. Indeed, while PEEP improves pulmonary compliance and arterial oxygenation, these effects only last in the first hours after surgery.61 This is also true for the prevention of atelectasis.62 In one trial in patients after cardiac surgery in which PEEP was titrated on the best achievable PaO2 level no sustained benefit was found.63 In general, intensive care unit clinicians now use PEEP levels between 4 and 7 cm H2O in critically ill patients who need ventilation for other reasons than ARDS,28 though the best level of PEEP for these patients remains unclear.
Positive end–expiratory pressure during intraoperative ventilationInduction of anaesthesia induces atelectasis,64 increasing ventilation–perfusion mismatch and suboptimal oxygenation.65 Intraoperative use of PEEP, with or without recruitment manoeuvres, is suggested to prevent atelectasis and repeated opening and closing of lung tissue.65 14 Indeed, use of higher levels of PEEP seems to improve oxygenation and respiratory mechanics in a wide range of patient populations and surgical settings.15, 66-74 However, in most trials of intraoperative PEEP, recruitment of lung tissue was not maintained in the postoperative period at the post anaesthesia care unit (PACU).72, 73
Benefit of higher levels of PEEP on postoperative outcome was suggested in the three randomized controlled trials of lung–protective intraoperative ventilation mentioned above, where use of low tidal volumes was actually combined with higher levels of PEEP with recruitment maneuvers.36-38 It is difficult, if not impossible to conclude what prevented postoperative complications: the use of low tidal volumes or the high levels of PEEP, or recruitment manoeuvres, or altogether. Despite this, both low tidal volumes and high levels of PEEP with recruitment manoeuvres are suggested to be beneficial.75 A recent large retrospective study confirms this suggestion, showing that both low tidal volumes (< 10 mL/kg) and higher PEEP levels (≥ 5 cmH2O) are independently associated with a decreased risk of postoperative respiratory complications.35
The lack of sufficient evidence for benefit of higher levels of PEEP during surgery is mirrored in the remarkable variation in use of intraoperative PEEP varying from 17% to as high as 82% of recently reported series.40-42, 44, 45
14
Oxygen fractions
Oxygen fractions in animal studiesThe potentially toxic effects of high fractions of inspired oxygen (FiO2) have long been known from animal studies. Mice exposed to hyperoxia develop a condition similar to ARDS, which is at least in part dependent on an increased production of reactive oxygen species (ROS) by mitochondria.76, 77 Hyperoxia could further cause atelectasis, tracheobronchitis, interstitial fibrosis, protein leakage and neutrophil infiltration.78-80 In spontaneous breathing rodents with pneumonia, hyperoxia has been shown to contribute to bacterial spread beyond the lungs,81 lung injury and even lethality.82 More cytokine production and increased lung injury was found in experiments in ventilated rodents with hyperoxia during injurious ventilation (tidal volume > 20 mL/kg).83-85
Oxygen fractions in patients with ARDSIn human lungs high FiO2 can also accelerate the production of ROS, which overwhelms natural anti–oxidant defences and injures cellular structures in the lung.9,16,86,87 Furthermore, hyperoxia can cause derecruitment of lung tissue by resorption atelectasis.88 Critically ill patients with lung injury are possibly more prone to the harmful pulmonary effects of oxygen toxicity, which can coincide with the primary pulmonary injury (e.g., ARDS, pneumonia) and ventilator–associated lung injury.77,89,90 One small trial found that 100% compared to 60% FiO2 increased development of atelectasis in patients with ARDS, which was prevented by application of higher levels of PEEP.91 However, clinical trials examining the effect of hyperoxia on the development of lung injury in patients with ARDS are lacking.
Oxygen fractions in critically ill patients without ARDSIn critical care patients who need ventilatory support for reasons other than ARDS, an association between hyperoxia and mortality was found in ventilated patients,89 patients after cardiac arrest,92 and patients with traumatic brain injury,93 or stroke.94 However, other studies did not reveal such associations.90, 95-97 For example, two recent metaanalyses investigating the effect of high FiO2 in critical care patients on survival showed mixed results.98, 99 One metaanalysis did not find a significant association in the general ICU,98 while another metaanalysis of pooled data from all critically ill patients suggested arterial hyperoxia to increase the risk of mortality.99 In subset analyses, hyperoxia was associated with decreased survival in patients after cardiac arrest, traumatic brain injury, and stroke.98 In patients after cardiac arrest a dose–dependent association between hyperoxia and patient outcome was found.99,100 Notably, arterial hyperoxia decreases coronary blood flow and cardiac output, increases systemic vascular resistance, and contributes to reperfusion injury in patients with myocardial infarction.101-104 A recent randomized controlled trial in patients with myocardial infarction indeed clearly showed that supplemental oxygen increased myocardial injury.105 Research on the effect of FiO2 on the development of lung injury in patients ventilated for other reasons than ARDS, however, is currently unavailable. Despite the lack of evidence, current guidelines in critically ill patients aim at PaO2 levels around 55–80 mm Hg.55,106
Oxygen fractions during intraoperative ventilationAnaesthesiologists use high FiO2 during pre–oxygenation and denitrogenation to prolong the apnoea tolerance time107 and during intraoperative ventilation to correct for arterial hypoxemia
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induced by ventilation–perfusion mismatches caused by alveolar collapse.64 High FiO2 (> 80%) increases the incidence of resorption atelectasis, which not only augments atelectasis formation after induction,107,108 but also directly before emergence from anaesthesia in the post–oxygenation phase, annulling the open lung created during intraoperative ventilation.109 At the same time, there is a risk of hyperoxia–induced injury to the lungs. The available trials and metaanalyses on perioperative hyperoxia focused on the beneficial effect of high FiO2 on postoperative nausea and vomiting110-112 and postoperative wound infections.113-118 A large trial on postoperative wound infections investigated the effect of 80% compared to 30% oxygen during surgery on development of postoperative pulmonary complications as secondary endpoint and found no difference in incidence of atelectasis, pneumonia, and respiratory failure.117 A clinical trial in obese patients showed worse postoperative lung function in patients receiving FiO2 during ventilation.119 One metaanalysis found no difference in presence or absence of atelectasis or postoperative gas exchange during intraoperative ventilation with either high or low FiO2.120 A large recent metaanalysis, however, suggested that hyperoxia was not associated with increased 30–day mortality.121 Sufficiently powered clinical trials on lung injury and postoperative pulmonary complications due to high FiO2 are lacking.
Aims of this thesis
This thesis is a collection of investigations that focused on several aspects of perioperative ventilation, specifically ventilation practice and the associations between ventilator settings and the effects on postoperative pulmonary complications and outcome. The main interest was on PEEP. We hypothesized that the use of higher PEEP and recruitment manoeuvres would protect against development of postoperative pulmonary complications during intraoperative ventilation.
The specific aims of this thesis were:
1. To investigate the effect of intraoperative use of PEEP and recruitment manoeuvres on occurrence of postoperative pulmonary complications during low tidal volume ventilation during open abdominal surgery.
2. To determine the association between intraoperative use of high tidal volumes, PEEP and recruitment manoeuvres, and the occurrence of postoperative pulmonary complications.
3. To investigate the effects of development of postoperative lung injury on postoperative clinical course and mortality.
4. To examine the effects of different levels of PEEP during postoperative ventilation after coronary artery bypass grafting on the duration to extubation.
16
Outline of this thesis
The following chapters in this thesis report on observational studies, clinical trials and metaanalyses that reported on several aspects of lung–protective perioperative ventilation, including effects of tidal volume size and level of PEEP.
Chapter 2 provides the results of a metaanalysis of eight clinical trials examining the effects of intraoperative ventilator settings on postoperative outcome of non–cardiac surgery patients. We hypothesized that use of low tidal volumes and/or PEEP with or without recruitment manoeuvres could prevent postoperative pulmonary complications, and as such improving postoperative outcome. In this metaanalysis we tried to separate the effects of tidal volume and PEEP manipulations.
Chapter 3 constitutes a comprehensive review of the literature on predictive models of postoperative pulmonary complications, the pathophysiology of ventilation–induced lung injury, and protective ventilation strategies, including the respective roles of tidal volume size, the level of PEEP and the use of recruitment manoeuvres. In this review we propose an algorithm for protective intraoperative mechanical ventilation.
In Chapter 4 and chapter 5 we describe the design and the results, respectively, of the ‘Local Assessment of Ventilatory Management during General Anaesthesia for Surgery’–study (LAS VEGAS), a prospective observational cohort study designed to assess intraoperative ventilation practice in Europe and the America’s, and to test the hypothesis that certain ventilator settings, especially high tidal volumes and low PEEP levels, are associated with the occurrence of postoperative pulmonary complications.
In Chapter 6 we show the results of a metaanalysis using individual patient data from 15 randomized controlled trials of intraoperative ventilation. We hypothesized that intraoperative ventilation with lower tidal volumes protects against postoperative pulmonary complications, and that use of higher levels of PEEP adds to the beneficial effects of lower tidal volumes.
Chapter 7 and chapter 8 constitute the design and results of the PROVHILO trial (High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery), a randomized controlled trial of intraoperative ventilation for open abdominal surgery. In chapter 9 entails letters with comments on PROVHILO written by peers, as well as our Author’s reply. In this trial patients were randomized to ventilation with high levels of PEEP (12 cm H2O) with recruitment manoeuvres or low levels of PEEP (0 to 2 cm H2O) without recruitment manoeuvres. We hypothesized that a ventilation strategy with high levels of PEEP and recruitment manoeuvres would protect against development of postoperative pulmonary complications.
In Chapter 10 we describe the results of another metaanalysis, using individual patient data from 12 clinical investigations of intraoperative ventilation. We hypothesized that the occurrence of postoperative lung injury was associated with a worse outcome, and that postoperative outcome would depend on intraoperative ventilation settings.
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In Chapter 11 we present the results of a secondary analysis of two randomized controlled trials of postoperative ventilation in patients undergoing cardiac surgery, in which we determined the effects of PEEP manipulations on pulmonary compliance and gas exchange in the first hours of weaning from mechanical ventilation and time on the ventilator.122, 123 We hypothesized that higher levels of PEEP would improve pulmonary function, but not to be associated with a shorter duration of postoperative ventilation.
This thesis ends with a summary of the abovementioned studies and a general discussion in chapter 12, with Dutch translation in chapter 13.
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72. Wetterslev J, Hansen EG, Roikjaer O, Kanstrup IL, Heslet L. Optimizing peroperative compliance with PEEP during upper abdominal surgery: effects on perioperative oxygenation and complications in patients without preoperative cardiopulmonary dysfunction. European journal of anaesthesiology 2001; 18(6): 358-65
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susceptibility to hyperoxic lung injury in mice. American journal of physiology Lung cellular and molecular physiology 2003; 285(1): L250-7
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78. Crapo JD. Morphologic changes in pulmonary oxygen toxicity. Annual review of physiology 1986; 48: 721-3179. Crapo JD, Barry BE, Foscue HA, Shelburne J. Structural and biochemical changes in rat lungs occurring during exposures
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pneumonia: the role of apoptosis. Journal of immunology 2003; 170(8): 4209-1683. Li LF, Liao SK, Ko YS, Lee CH, Quinn DA. Hyperoxia increases ventilator-induced lung injury via mitogen-activated protein
kinases: a prospective, controlled animal experiment. Critical care 2007; 11(1): R2584. Makena PS, Luellen CL, Balazs L, et al. Preexposure to hyperoxia causes increased lung injury and epithelial apoptosis
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86. Aggarwal NR, Brower RG. Targeting normoxemia in acute respiratory distress syndrome may cause worse short-term outcomes because of oxygen toxicity. Annals of the American Thoracic Society 2014; 11(9): 1449-53
87. Barazzone C, White CW. Mechanisms of cell injury and death in hyperoxia: role of cytokines and Bcl-2 family proteins. American journal of respiratory cell and molecular biology 2000; 22(5): 517-9
88. Edmark L, Auner U, Enlund M, Ostberg E, Hedenstierna G. Oxygen concentration and characteristics of progressive atelectasis formation during anaesthesia. Acta Anaesthesiologica Scandinavica 2011; 55(1): 75-81
89. de Jonge E, Peelen L, Keijzers PJ, et al. Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients. Critical Care 2008; 12(6): R156
90. Eastwood G, Bellomo R, Bailey M, et al. Arterial oxygen tension and mortality in mechanically ventilated patients. Intensive Care Medicine 2012; 38(1): 91-8
91. Aboab J, Jonson B, Kouatchet A, Taille S, Niklason L, Brochard L. Effect of inspired oxygen fraction on alveolar derecruitment in acute respiratory distress syndrome. Intensive Care Medicine 2006; 32(12): 1979-86
92. Kilgannon JH, Jones AE, Shapiro NI, et al. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. Jama 2010; 303(21): 2165-71
93. Brenner M, Stein D, Hu P, Kufera J, Wooford M, Scalea T. Association between early hyperoxia and worse outcomes after traumatic brain injury. Archives of surgery 2012; 147(11): 1042-6
94. Rincon F, Kang J, Maltenfort M, et al. Association between hyperoxia and mortality after stroke: a multicenter cohort study. Critical Care Medicine 2014; 42(2): 387-96
95. Bellomo R, Bailey M, Eastwood GM, et al. Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest. Critical care 2011; 15(2): R90
96. Young P, Beasley R, Bailey M, et al. The association between early arterial oxygenation and mortality in ventilated patients with acute ischaemic stroke. Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine 2012; 14(1): 14-9
97. Raj R, Bendel S, Reinikainen M, et al. Hyperoxemia and long-term outcome after traumatic brain injury. Critical Care 2013; 17(4): R177
98. Damiani E, Adrario E, Girardis M, et al. Arterial hyperoxia and mortality in critically ill patients: a systematic review and metaanalysis. Critical care 2014; 18(6): 711
99. Helmerhorst HJ, Roos-Blom MJ, van Westerloo DJ, de Jonge E. Association Between Arterial Hyperoxia and Outcome in Subsets of Critical Illness: A Systematic Review, Metaanalysis, and Meta-Regression of Cohort Studies. Critical Care Medicine 2015
100. Wang CH, Chang WT, Huang CH, et al. The effect of hyperoxia on survival following adult cardiac arrest: a systematic review and metaanalysis of observational studies. Resuscitation 2014; 85(9): 1142-8
101. Farquhar H, Weatherall M, Wijesinghe M, et al. Systematic review of studies of the effect of hyperoxia on coronary blood flow. American heart journal 2009; 158(3): 371-7
102. Kenmure AC, Murdoch WR, Beattie AD, Marshall JC, Cameron AJ. Circulatory and metabolic effects of oxygen in myocardial infarction. British medical journal 1968; 4(5627): 360-4
103. McNulty PH, Robertson BJ, Tulli MA, et al. Effect of hyperoxia and vitamin C on coronary blood flow in patients with ischemic heart disease. Journal of applied physiology 2007; 102(5): 2040-5
104. Mak S, Azevedo ER, Liu PP, Newton GE. Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure. Chest 2001; 120(2): 467-73
105. Stub D, Smith K, Bernard S, et al. Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction. Circulation 2015; 131(24): 2143-50
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106. Patroniti N IG. Mechanical ventilation—Skills and techniques. Patient-centered Acute Care Training (PACT) Module—European Society of Intensive Care Medicine 2015
107. Edmark L, Kostova-Aherdan K, Enlund M, Hedenstierna G. Optimal oxygen concentration during induction of general anesthesia. Anesthesiology 2003; 98(1): 28-33
108. Hedenstierna G. Oxygen and anesthesia: what lung do we deliver to the post-operative ward? Acta Anaesthesiologica Scandinavica 2012; 56(6): 675-85
109. Benoit Z, Wicky S, Fischer JF, et al. The effect of increased FiO2 before tracheal extubation on postoperative atelectasis. Anesthesia and Analgesia 2002; 95(6): 1777-81, table of contents
110. Greif R, Laciny S, Rapf B, Hickle RS, Sessler DI. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999; 91(5): 1246-52
111. Orhan-Sungur M, Kranke P, Sessler D, Apfel CC. Does supplemental oxygen reduce postoperative nausea and vomiting? A metaanalysis of randomized controlled trials. Anesthesia and analgesia 2008; 106(6): 1733-8
112. Simurina T, Mraovic B, Mikulandra S, et al. Effects of high intraoperative inspired oxygen on postoperative nausea and vomiting in gynecologic laparoscopic surgery. Journal of clinical anesthesia 2010; 22(7): 492-8
113. Scifres CM, Leighton BL, Fogertey PJ, Macones GA, Stamilio DM. Supplemental oxygen for the prevention of postcesarean infectious morbidity: a randomized controlled trial. American journal of obstetrics and gynecology 2011; 205(3): 267 e1-9
114. Greif R, Akca O, Horn EP, Kurz A, Sessler DI. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. NEJM 2000; 342(3): 161-7
115. Qadan M, Akca O, Mahid SS, Hornung CA, Polk HC, Jr. Perioperative supplemental oxygen therapy and surgical site infection: a metaanalysis of randomized controlled trials. Archives of surgery 2009; 144(4): 359-66
116. Pryor KO, Fahey TJ, 3rd, Lien CA, Goldstein PA. Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population: a randomized controlled trial. JAMA 2004; 291(1): 79-87
117. Meyhoff CS, Wetterslev J, Jorgensen LN, et al. Effect of high perioperative oxygen fraction on surgical site infection and pulmonary complications after abdominal surgery: the PROXI randomized clinical trial. JAMA 2009; 302(14): 1543-50
118. Bustamante J, Tamayo E, Alvarez FJ, et al. Intraoperative PaO2 is not related to the development of surgical site infections after major cardiac surgery. Journal of cardiothoracic surgery 2011; 6: 4
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120. Hovaguimian F, Lysakowski C, Elia N, Tramer MR. Effect of intraoperative high inspired oxygen fraction on surgical site infection, postoperative nausea and vomiting, and pulmonary function: systematic review and metaanalysis of randomized controlled trials. Anesthesiology 2013; 119(2): 303-16
121. Wetterslev J, Meyhoff CS, Jorgensen LN, Gluud C, Lindschou J, Rasmussen LS. The effects of high perioperative inspiratory oxygen fraction for adult surgical patients. The Cochrane Database of Systematic Reviews 2015; 6: CD008884
122. Dongelmans DA, Veelo DP, Paulus F, et al. Weaning automation with adaptive support ventilation: a randomized controlled trial in cardiothoracic surgery patients. Anesthesia and Analgesia 2009; 108(2): 565-71
123. Dongelmans DA, Veelo DP, Binnekade JM, et al. Adaptive support ventilation with protocolized de-escalation and escalation does not accelerate tracheal extubation of patients after nonfast-track cardiothoracic surgery. Anesthesia and Analgesia 2010; 111(4): 961-7
General introduction
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Chapter 2
Intraoperative Ventilatory Strategies to Prevent Postoperative Pulmonary Complications – a Metaanalysis
Hemmes SNT, Serpa Neto A, Schultz MJ Current Opinion in Anesthesiology 2013; 26(2):126-33
26
Abstract
Purpose. It is uncertain whether patients undergoing short–lasting mechanical ventilation for surgery benefit from lung–protective intraoperative ventilatory settings including the use of lower tidal volumes, higher levels of positive end–expiratory pressure (PEEP) and/or recruitment manoeuvres (RM). We meta–analysed trials testing the effect of lung–protective intraoperative ventilatory settings on the incidence of postoperative pulmonary complications.
Recent findings. Eight articles (1669 patients) were included. Metaanalysis showed a decrease in lung injury development (risk ratio [RR] 0.40; 95% CI 0.22–0.70; I2 0%; number needed to treat [NNT] 37), pulmonary infection (RR 0.64; 95% CI 0.43–0.97; I2 0%; NNT 27) and atelectasis (RR 0.67; 95% CI 0.47–0.96; I2 48%; NNT 31) in patients receiving intraoperative MV with lower tidal volumes. Metaanalysis also showed a decrease in lung injury development (RR 0.29; 95% CI 0.14–0.60; I2 0%; NNT 29), pulmonary infection (RR 0.62; 95% CI 0.40–0.96; I2 15%; NNT 33) and atelectasis (RR 0.61; 95% CI 0.41–0.91; I2 0%; NNT 29) in patients ventilated with higher levels of PEEP, with or without RM.
Summary. Lung–protective intraoperative ventilatory settings may have the potential to protect against postoperative pulmonary complications.
Mechanical ventilation (MV) has the potential to cause so–called ventilator–associated lung injury (VALI). VALI results from overdistention of non–dependent lung tissue causing excessive cyclic strain of alveolar cells,1 and repetitive opening and closing of dependent lung tissue resulting in cyclic cell stress due to the extreme forces exposed to lung cells at the interfaces between open and closed alveoli.2,3 Lung–protective MV with use of lower tidal volumes, which is suggested to prevent alveolar overdistention, benefits critically ill patients suffering from acute respiratory distress syndrome (ARDS).4 MV with higher levels of positive end–expiratory pressure (PEEP) with or without recruitment manoeuvres (RM), which is suggested to prevent repetitive opening and closing of alveoli, also seems beneficial at least in patients with severe ARDS.4 Recent clinical studies suggest MV with lower tidal volumes even to benefit critically ill patients without ARDS.5-7
MV is an essential supportive strategy during general anaesthesia for surgery. It is uncertain whether short–lasting MV during surgery also has the potential to cause VALI.8 However, both animal and human studies show VALI can develop shortly after initiation of MV.7,9,10 In addition, general anaesthesia causes large atelectasis, especially when muscle relaxants are used.11 As a consequence, there is an increased risk of overdistention of non–atelectatic lung tissue as well as repetitive opening and closing of partly atelectatic lung tissue. Thus, patients who need MV for surgery may also be vulnerable to the harmful effects of MV. Notably, surgical patients frequently suffer from postoperative pulmonary complications, with reported incidences of up to 5.0%.12,13 It is tempting to speculate on a causal relation between these complications and intraoperative ventilatory settings.
We hypothesize use of intraoperative lung–protective ventilatory settings to lower the incidence of postoperative pulmonary complications, and consequently on the postoperative clinical course and length of hospital stay. To test this hypothesis, we meta–analysed clinical trials of MV for surgery, focusing on the use of lower tidal volumes and/or higher levels of PEEP and RM. This is a secondary metaanalysis of a previously published metaanalysis of clinical trials testing lung–protective MV in patients who received short–term MV (i.e., in the operation room for surgery) or long–term MV (i.e., in the intensive care unit because of critical illness).14 The present metaanalysis is restricted to the clinical trials in the operation room.
Methods
We searched Medline (1966–2012), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL). All reviewed articles and cross–referenced studies from retrieved articles were screened for pertinent information. Articles were selected for inclusion in the metaanalysis if they evaluated two types of MV in patients with uninjured lungs undergoing surgery. In one arm of the trial, MV should be protective (lower tidal volumes, and/or higher levels of PEEP with or without use of RMs). Then, this protective strategy should be compared with conventional methods
28
(higher tidal volumes, and no or lower levels of PEEP and no use of RMs) in the other arm of the trial. We excluded trials of patients undergoing cardiac surgery. We also excluded revisions and trials that did not report the outcomes of interest (defined below). When we found duplicate articles of the same trial in preliminary abstracts and articles, we analysed data from the most complete data set.
Data were extracted from each article using a data recording form developed for the previously published metaanalysis.14 After extraction, data were reviewed and compared by the second author. Whenever needed, we obtained additional information about a specific study by directly questioning the principal investigator of the specific trial.
The primary endpoint was the incidence of lung injury in each arm of the trial. Secondary endpoints included incidence of pulmonary infection (using the authors’ definition) or atelectasis. Statistical analysis was performed as described in the original metaanalysis.14
Results
The initial search yielded 2.123 articles (459 from MEDLINE, 141 from CENTRAL, 885 from CINAHL, and 638 from Web of Science) (figure 1). After removing 711 duplicate articles, we evaluated the abstracts of 1.412 articles. After evaluating them, 1.364 articles were excluded because they did not meet inclusion criteria. Another five articles were excluded because MV was applied for other reasons than surgery, no data on outcome of interest was reported in 28, and same cohort previously analysed in seven. Finally, eight articles were included in the final analysis.15-22
Tidal volume reductionOur search of the literature revealed eight articles (1669 patients) reporting on trials comparing lower with conventional tidal volumes during surgery (table 1 and table 2). Metaanalysis of these trials showed that 17 of 858 patients (2.0%) ventilated with lower tidal volumes and 36 of 755 patients (4.7%) ventilated with conventional tidal volumes developed lung injury during follow-up (risk ratio [RR] 0.40; 95% confidence interval [CI] 0.22–0.70; number needed to treat [NNT] 37) (figure 2). The analysis displayed no signs of heterogeneity (I2 = 0%). Pulmonary infection and atelectasis showed lower incidence in patients receiving lower tidal volume ventilation (RR 0.64; 95% CI 0.43–0.97; NNT 27 and RR 0.67; 95% CI 0.47–0.96; NNT 31, respectively). The I2 test indicated no heterogeneity in the analysis of pulmonary infection, but moderate heterogeneity in the analysis of atelectasis (0% and 48% respectively).
Higher levels of PEEP and RMsOur search of the literature revealed five articles (1323 patients) reporting on trials comparing no or lower levels of PEEP (up to 3 cmH2O) with higher levels of PEEP (from 3 to 12 cmH2O) during surgery (table 1).
Metaanalysis of these trials shows that 9 of 654 patients (1.4%) ventilated with higher levels of PEEP developed postoperative lung injury compared to 31 of 629 patients (4.9%) receiving
lower levels of PEEP (RR 0.29; 95% CI 0.14–0.60; NNT 29) (figure 3), without any signs for heterogeneity within the analysis (I2 = 0%). A beneficial effect of higher levels of intraoperative PEEP on postoperative pulmonary infection and atelectasis was also found (RR 0.62; 95% CI 0.40–0.96; NNT 33 and RR 0.61; 95% CI 0.41–0.91; NNT 29, respectively). The I2 test indicated moderate heterogeneity in the analysis of pulmonary infection, but not in the analysis of atelectasis (15% and 0% respectively). We did not find trials specifically investigating exclusively the effects of intraoperative RM.
Mean ± standard deviation; IBW: ideal body weight; PEEP: positive end expiratory pressure; a: in the final of the follow-up
Discussion
This metaanalysis suggests that intraoperative MV with lower tidal volumes may protect surgical patients from development of postoperative lung injury, pulmonary infections and atelectasis. This metaanalysis also suggests that intraoperative use of higher levels of PEEP during MV attenuates development of lung injury, pulmonary infection and atelectasis.
Implementation of lung–protective MV for surgery has the potential to significantly reduce postoperative pulmonary complications. Considering the high number of surgical procedures performed worldwide daily,23 reduction of postoperative pulmonary complications could be of great importance. Notably, a recent international prospective trial shows the incidence of postoperative mortality to be as high as 4%, much higher than previously assumed.24 A large international observational study is underway to address the effect of intraoperative ventilatory settings on postoperative complications.25
Prescription of MV in critically ill patients has definitely changed over the last decades. There has been progressive reduction of tidal volume size, from > 12 ml/kg in the 1970s 26,27 to < 9 ml/kg in more recent epidemiologic studies of MV practice in Europe and the Americas.28-31 This change was largely stimulated by results from animal studies, which clearly show injurious tidal volume settings to aggravate pre–existing pulmonary injury.9 Several clinical trials confirm the existence of VALI by showing reduced morbidity and mortality in patients with ARDS ventilated with lower tidal volumes.4 While initially intensive care unit physicians have been reluctant to use lower tidal volumes as part of their MV strategy, guidelines now strongly support the use
of lower tidal volumes in patients with ARDS, e.g., in patients with sepsis.32 Critically ill patients without ARDS also seem to benefit from ventilation with lower tidal volumes.5,6 One recent randomized controlled trial shows a lower tidal volume strategy to protect against lung injury in patients without ARDS at onset of MV in the intensive care unit.7
Notably, a recent observational study in patients undergoing short–term postoperative MV after cardiac surgery shows MV with tidal volumes > 10 ml/kg to be associated with prolonged MV, hemodynamic instability, multiple organ failure, and prolonged stay in the ICU, compared to MV with lower tidal volumes. In this study women and obese patients are found to be particularly at risk of receiving ventilation with too large tidal volumes.33 These results confirm, at least in part findings from another recent study that identifies female gender, overweight and underweight as independent factors for MV with too large tidal volumes.34
MV with lower tidal volumes may not come without challenges. Use of lower tidal volumes could increase cyclic alveolar collapse of dependent lung regions, raising the risk of atelectrauma. Application of PEEP is an easy intervention that may counteract this side–effect of lower tidal volume ventilation. Lower tidal volume ventilation could also lead to hypercapnia and hypercapnic acidosis. Notably, so-called permissive hypercapnia is thought to have lung–protective qualities,
Figure 3. Effect of intraoperative ventilation with higher levels of PEEP
34
even though the exact clinical implications are not entirely clear.35
Prescription of PEEP in critically ill patients has also changed over the last decades. PEEP is progressively more frequent applied in intubated and mechanically ventilated patients in the intensive care unit, with an increase in use of PEEP levels > 10 cmH2O from 28% in the late ‘90s 28,29 to 40% in a more recent survey across ICUs in Europe and the Americas.36 Particularly in patients with ARDS higher levels of PEEP are being applied, even though the benefits of higher PEEP levels with or without RM are not unequivocally demonstrated.28,29,36 Use of higher levels of PEEP and RM could benefit patients with severe ARDS, though .4,37 Trials investigating the effects of higher levels of PEEP in critically ill patients without ARDS are lacking. The results of the present metaanalysis are in line with results from a previous systematic review suggesting higher levels of PEEP to reduce postoperative atelectasis.38
None of the trials included in our metaanalysis analysed the effect of RM separate from the use of higher levels of PEEP. However, one recent randomized controlled trial of cardiac surgery patients shows decrease of alveolar dead–space and increase in arterial oxygenation during surgery when RMs are performed.39
An adversity of use of higher levels of PEEP, with or without the use of RM, may lay in an increase in right ventricular afterload as well as a decrease in right ventricular preload. This could cause a decrease in left ventricular preload and reduction in left ventricular stroke volume.40 It is uncertain whether this causes problems in patients undergoing surgery.
Our study knows several shortcomings. First, it is difficult if not impossible to differentiate between the beneficial effect from lower tidal volumes and that from higher levels of PEEP with or without RM. Most trials included in this metaanalyses compared “conventional ventilation” with higher tidal volumes and low levels of PEEP with a “lung-protective” MV strategy with lower tidal volume ventilation and higher levels of PEEP (table 1). As a result all trials included in the metaanalysis assessing the effect of higher levels of PEEP and RM is also part of the metaanalysis analysing the effect of lower tidal volumes. Second, the incidence of lung injury could very well be higher than calculated in this metaanalysis, as the clinical picture of ARDS often resembles “suspected” pulmonary infection. ARDS as well as pulmonary infection may present with leucocytosis, fever and pulmonary infiltrates on the chest radiograph. Thus, it could be that ARDS is mistakenly diagnosed as pulmonary infection in some cases. Finally, when interpreting the results of this metaanalysis, the possible occurrence of positive publication bias should be taken into account. Furthermore the use of funnel plots has a limited role, as test for bias when the number of studies included in the analysis is small. Despite these limitations, our metaanalysis provides interesting information which needs further exploration.
Lower tidal volumes, higher levels of PEEP and RM are increasingly used in intensive care unit patients receiving long–term MV. Intraoperative use of lower tidal volumes could reduce the incidence of postoperative lung injury, pulmonary infections and atelectasis. Intraoperative use of higher levels of PEEP and RMs also reduce the incidence of these complications. It is difficult if not impossible to separate the beneficial effects of lower tidal volumes from that of higher levels of PEEP and RM. To better establish the effect of lung–protective intraoperative ventilatory settings we are also in need of well–powered randomized clinical trials. Presently, one large multicentre trial is conducted to identify the effect of intraoperative use of higher levels of PEEP and RM on the incidence of postoperative complications in adult surgical patients.41
Key points
1. Intraoperative use of lower tidal volumes may reduce postoperative lung injury, pulmonary infections and atelectasis
2. It is uncertain whether higher levels of PEEP, with or without use of RM, adds to the beneficial effects of intraoperative use of lower tidal volumes
3. We are in need of well–powered randomized controlled trials that test the effect of intraoperative lung–protective ventilatory settings, including tidal volume size, higher levels of PEEP and RM.
36
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in the absence of pre-existing lung injury in healthy mice. Crit Care 2009; 13: R111. Duggan M, Kavanagh BP. Pulmonary atelectasis: a pathogenic perioperative entity. Anesthesiology 2005; 102: 838-5412. Smetana GW, Lawrence VA, Cornell JE. Preoperative pulmonary risk stratification for noncardiothoracic surgery:
systematic review for the American College of Physicians. Ann Intern Med 2006; 144: 581-9513. Canet J, Gallart L, Gomar C, et al. Prediction of Postoperative Pulmonary Complications in a Population-based Surgical
Cohort. Anesthesiology 2010; 113: 1338-5014. Serpa Neto A, Cardoso SO, Manetta JA, et al. Association between use of lung-protective ventilation with lower tidal
volumes and clinical outcomes among patients without acute respiratory distress syndrome: a metaanalysis. JAMA 2012; 308: 1651-9
15. Michelet P, D’Journo XB, Roch A, et al. Protective ventilation influences systemic inflammation after esophagectomy: a randomized controlled study. Anesthesiology 2006; 105: 911-9
16. Cai H, Gong H, Zhang L, et al. Effect of low tidal volume ventilation on atelectasis in patients during general anesthesia: a computed tomographic scan. J Clin Anesth 2007; 19: 125-9
17. Lin WQ, Lu XY, Cao LH, et al. [Effects of the lung protective ventilatory strategy on proinflammatory cytokine release during one-lung ventilation]. Ai Zheng 2008; 27: 870-3
18. Licker M, Diaper J, Villiger Y, et al. Impact of intraoperative lung-protective interventions in patients undergoing lung cancer surgery. Crit Care 2009; 13: R41
19. Weingarten TN, Whalen FX, Warner DO, et al. Comparison of two ventilatory strategies in elderly patients undergoing major abdominal surgery. Br J Anaesth 2010; 104: 16-22
20. Fernandez-Bustamante A, Wood CL, Tran ZV, et al. Intraoperative ventilation: incidence and risk factors for receiving large tidal volumes during general anesthesia. BMC Anesthesiol 2011; 11: 22
21. Yang M, Ahn HJ, Kim K, et al. Does a protective ventilation strategy reduce the risk of pulmonary complications after lung cancer surgery?: a randomized controlled trial. Chest 2011; 139: 530-7
22. Treschan TA, Kaisers W, Schaefer MS, et al. Ventilation with low tidal volumes during upper abdominal surgery does not improve postoperative lung function. Br J Anaesth 2012; 109: 263-71
23. Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet 2008; 372: 139-44
24. Pearse RM, Moreno RP, Bauer P, et al. Mortality after surgery in Europe: a 7 day cohort study. Lancet 2012 380: 1059-6525. ClinicalTrials.gov. (2012) Local Assessment of Ventilatory Management During General Anesthesia for Surgery (LAS
VEGAS), NCT01601223. http://clinicaltrials.gov/ct2/show/NCT01601223?term=las+vegas&rank=1 26. Suter PM, Fairley B, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute pulmonary failure.
NEJM 1975; 292: 284-927. Jardin F, Farcot JC, Boisante L, et al. Influence of positive end-expiratory pressure on left ventricular performance.
NEJM 1981; 304: 387-9228. Esteban A, Anzueto A, Alia I, et al. How is mechanical ventilation employed in the intensive care unit? An international
utilization review. Am J Respir Crit Care Med 2000; 161: 1450-829. Esteban A, Anzueto A, Frutos F, et al. Characteristics and outcomes in adult patients receiving mechanical ventilation:
a 28-day international study. JAMA 2002; 287: 345-55
30. Brun-Buisson C, Minelli C, Bertolini G, et al. Epidemiology and outcome of acute lung injury in European intensive care units. Results from the ALIVE study. Intensive Care Med 2004; 30: 51-61
31. Sakr Y, Vincent JL, Reinhart K, et al. High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury. Chest 2005; 128: 3098-108
32. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36: 296-327
33. Lellouche F, Dionne S, Simard S, et al. High tidal volumes in mechanically ventilated patients increase organ dysfunction after cardiac surgery. Anesthesiology 2012; 116: 1072-82
34. Jaber S, Coisel Y, Chanques G, et al. A multicentre observational study of intra-operative ventilatory management during general anaesthesia: tidal volumes and relation to body weight. Anaesthesia 2012; 67: 999-1008
35. Ismaiel NM, Henzler D. Effects of hypercapnia and hypercapnic acidosis on attenuation of ventilator-associated lung injury. Minerva Anestesiol 2011; 77: 723-33.
36. Esteban A, Ferguson ND, Meade MO, et al. Evolution of mechanical ventilation in response to clinical research. Am J Respir Crit Care Med 2008; 177: 170-7
37. Gattinoni L, Caironi P. Refining ventilatory treatment for acute lung injury and acute respiratory distress syndrome. JAMA 2008; 299: 691-3
38. Imberger G, McIlroy D, Pace NL, et al. Positive end-expiratory pressure (PEEP) during anaesthesia for the prevention of mortality and postoperative pulmonary complications. Cochrane Database Syst Rev 2010: CD007922
39. Unzueta C, Tusman G, Suarez-Sipmann F, et al. Alveolar recruitment improves ventilation during thoracic surgery: a randomized controlled trial. Br J Anaesth 2012; 108: 517-24
40. Luecke T, Pelosi P. Clinical review: Positive end-expiratory pressure and cardiac output. Crit Care 2005; 9: 607-2141. Hemmes SN, Severgnini P, Jaber S, et al. Rationale and study design of PROVHILO - a worldwide multicenter randomized
controlled trial on protective ventilation during general anesthesia for open abdominal surgery. Trials 2011; 12: 111
Chapter 3
Intraoperative Protective Mechanical Ventilation for Prevention of Postoperative Pulmonary ComplicationsA Comprehensive Review of the Role of Tidal Volume, Positive End-Expiratory Pressure and Lung Recruitment Manoeuvres
Güldner A, Kiss T, Serpa Neto A, Hemmes SNT, Canet J, Spieth PM, Rocco PRM, Schultz MJ, Pelosi P, Gama de Abreu M. Anesthesiology 2015; 123(3): 692-713
40
Abstract
Postoperative pulmonary complications are associated with increased morbidity, length of hospital stay, and mortality following major surgery. Intraoperative lung-protective mechanical ventilation has the potential to reduce the incidence of postoperative pulmonary complications. This review discusses the relevant literature on definition of and methods to predict occurrence of postoperative pulmonary complication, the pathophysiology of ventilator-induced lung injury with emphasis to the non-injured lung, and protective ventilation strategies, including the respective roles of tidal volumes, positive end-expiratory pressure and recruitment manoeuvres. The authors propose an algorithm for protective intraoperative mechanical ventilation based upon evidence from recent randomized clinical trials.
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Introduction
Postoperative pulmonary complications (PPCs) can have an important impact on the morbidity and mortality of patients who need major surgery.1 Approximately 5% of patients undergoing general surgery will develop a PPC and one of five patients who developed a PPC die within 30 days of surgery.1 Furthermore, the number of PPCs is strongly associated with postoperative length of stay and short-term and long-term mortality.1,2
There is growing evidence that intraoperative lung-protective mechanical ventilation using low tidal volumes, with or without high levels of positive end–expiratory pressure (PEEP) and recruitment manoeuvres, prevents PPCs compared to mechanical ventilation with high tidal volumes and low levels of PEEP without recruitment maneuvers.3-6
In the present article, we review the definition of and methods to predict PPCs, the patho-physiology of ventilator-induced lung injury (VILI) with emphasis on the non-injured lung, and ventilation strategies to minimize PPCs. To identify the most recent evidence from the literature on randomized clinical trials (RCTs) addressing intraoperative mechanical ventilation and non-clinical as well as clinical postoperative outcome measures, we conducted a MEDLINE review using the following search terms: (‘lower tidal volume’ OR ‘low tidal volume’ OR ‘protective ventilation’ OR ‘recruitment manoeuvres’ OR ‘PEEP’ OR ‘positive end expiratory pressure’). Retrieved articles, and cross–referenced studies from those articles, were screened for pertinent information.
Definition and prediction of postoperative pulmonary complications Summary of current definitionsPPCs are usually presented as a composite, which then includes possible fatal and non-fatal respiratory events of new onset occurring in the postoperative period. Currently, there is no agreement about which of these events should be considered as PPC, for example respiratory failure, lung injury, pneumonia, prolonged or unplanned mechanical ventilation or intubation, hypoxemia, atelectasis, bronchospasm, pleural effusion, pneumothorax, ventilatory depression, and aspiration pneumonitis.7,8 From a clinical standpoint, it is worthwhile to present PPCs as a composite, because any of these events alone or their associations has a significant impact on the postoperative outcome,1 using different definitions. However, it is clear that these events can have different pathophysiologic mechanisms. For this reason, some studies have focused on single events, mainly respiratory failure9 and pneumonia.10
PPCs, to be considered as such, must be related to anesthesia and/or surgery. Furthermore, the time frame must be well defined. Usually, an event is only considered as PPC if it develops within 5 to 7 days after surgery.8,11
42
Prediction of Postoperative Pulmonary ComplicationsPrediction of PPCs, or any of the single postoperative respiratory events that is part of that composite, can be useful to plan perioperative strategies aiming at their prevention, and also to reduce health system costs.12 First, the risk factors associated with the development of PPCs must be identified. In 2006, the American College of Physicians published a systematic review of the literature listing a number of risk factors for PPCs according to their respective levels of evidence.13 In recent years, that list has been expanded to include other factors found to increase the risk of PPCs. Table 1 depicts risk factors associated with PPCs according to the current literature. Approximately 50% of the risk for PPCs are attributable to the patient’s health conditions, while the other 50% are related to the surgical procedure and the anaesthetic management itself.1
Table 1. Risk factors for postoperative pulmonary complications
Patient characteristics Preoperative testing Surgery Anaesthetic management
Age Low albumin Open thoracic surgery General anesthesia
Male sex Low SpO2 (≤ 95%) Cardiac surgery High respiratory driving pressure (≥ 13 cmH2O)
ASA class ≥ 3 Anaemia (Hb < 10 g/dL) Open upper abdominal surgery High inspiratory oxygen fraction
Previous respiratory infection
Major vascular surgery
High volume of crystalloid administration
Functional dependency Neurosurgery Red blood cell transfusion
COPD Duration of surgery > 2h Nasogastric tube use
Smoking Emergent surgery
Renal failure
Gastroesophageal reflux disease
Weight loss
ASA, American Society of Anesthesiologists; COPD, chronic obstructive pulmonary disease; Hb, haemoglobin concentration; PPCs, postoperative pulmonary complications; SpO2, oxygen saturation as measured by pulse oximetry. Respiratory driving pressure, defined as inspiratory plateau airway pressure minus positive end-expiratory pressure
Based on risk factors, different scores have been developed that have the potential to predict the occurrence of PPCs,6,14-16 as shown in table 2. However, their applicability may be limited since they were derived from restricted settings,16 retrospective databases,15 or only validated for specific PPCs.6,14 The Assess Respiratory RIsk in Surgical Patients in CATalonia (ARISCAT) study was conducted in a general surgical population of Catalonia, Spain.1 After a multivariate analysis, a score based on seven risk factors was developed and underwent internal validation, showing
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a clinically relevant predictive capability (c-statistic, 0.90). Recently, the ARISCAT score was externally validated in a large European surgical sample (the Prospective Evaluation of a RIsk Score for Postoperative Pulmonary COmPlications in Europe, PERISCOPE study).2 Although differences in the performance of the ARISCAT score have been observed between European geographic areas, the score was able to discriminate three levels of PPCs risk (low, intermediate and high). Thus, at present, the ARISCAT score may represent the most valuable tool for predicting PPCs across different countries and surgical populations.
Putative mechanisms of ventilator-induced lung injury
The coexistence of closed, recruitable and already overdistended alveolar regions makes the lung vulnerable to detrimental effects of mechanical stress and strain induced by mechanical ventilation.17,18 The physical forces in some alveolar regions may exceed the elastic properties of the lungs although gross measurements of airway pressures or lung mechanics as usually monitored under anesthesia still suggest mechanical ventilation is in a “safe” zone.19,20 Several mechanisms have been postulated to describe the development of VILI.21 Increased airway pressure (barotrauma) or the application of high tidal volumes (volutrauma) may cause damage or disruption of alveolar epithelial cells, by generating transpulmonary pressures (stress) that exceed the elastic properties of the lung parenchyma above its resting volume (strain).22,23 It has been demonstrated that the duration of mechanical stress defined as the stress versus time product affects the development of pulmonary inflammatory response.24 While high stress versus time product increased the gene expression of biological markers associated with inflammation and alveolar epithelial cell injury and low stress versus time product increased the molecular markers of endothelial cell damage, balanced stress versus time product as defined by an inspiratory to expiratory time ratio of 1:1 was associated with attenuated lung damage.24 Especially in the presence of atelectasis, mechanical ventilation may cause damage by repetitive collapse and reopening of alveolar units, a phenomenon known as atelectrauma.25 All three mechanisms, namely barotrauma, volutrauma and atelectrauma may affect alveolar as well as vascular epithelial and endothelial cells26,27 as well as promote extracellular matrix fragmentation.28,29
The extracellular matrix of the lung parenchyma seems to be particularly sensitive to stress from mechanical ventilation, as illustrated in figure 1. Initially, the proteoglycans on the endothelial side and between the endothelial and epithelial lines undergo damage dependent on tidal volume,28 as well as breathing pattern.29 The mechanical fragmentation of the extracellular matrix promotes interstitial oedema and activation of metalloproteinases, further damaging the extracellular matrix itself. In a second step, fragments of the extracellular matrix can promote activation of inflammatory mediators.30,31 Furthermore, the damage of the extracellular matrix induced by mechanical ventilation might be exacerbated by fluid load,32 which is not uncommon during general anesthesia. However, fluid overload seems to minimize the inflammatory response, likely by dilution of extracellular matrix fragments or changes in their structure, thereby down regulating the local inflammatory response.32 This suggests that: 1) injurious mechanical ventilation makes the lung more susceptible to further insults; 2) in previously healthy lungs, VILI can be induced without early increase in inflammatory mediators.
At the cellular level, physical stimuli are transformed into chemical signals, e.g. pro- and anti-inflammatory mediators by means of direct cell injury or indirect activation of cellular signalling pathways. This process is known as “mechanotransduction”.33 Some mediators may promote local effects such as pro-apoptotic or pro-fibrotic actions, while others act as homing molecules recruiting local and remote immune cell populations (e.g. neutrophils and macrophages).34 These local effects as well as their immunological consequences are summarized by the term “biotrauma”.35
Besides the extracellular matrix, both the endothelial and the epithelial compartment of the alveolar-capillary unit are affected by stress and strain originating from mechanical ventilation. In the endothelium, high stress can lead to direct cell breaks, resulting in capillary stress failure.36,37 Furthermore, mechanical stress as well as inflammatory stimuli (i.e. TNF alpha) may trigger contractions of the cytoskeleton 38 resulting in disruption of adherence junctions,39 which increase endothelial permeability and contribute to oedema formation. Similar to the pulmonary endothelium, mechanical stress and strain increase the permeability of the alveolar epithelium,40 a phenomenon found during ventilation at high,41 as well as low42 lung volumes. Additionally, low lung volume ventilation can lead to repetitive collapse and reopening of lung, affecting the epithelium of small airways, yielding plasma membrane disruption,43 as well as epithelial necrosis and sloughing.44
Figure 1. Alterations of the extracellular matrix in lungs during mechanical ventilation and fluid administration
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Alveolar fluid clearance is essential to maintain intra-alveolar fluid homeostasis, which is usually compromised during VILI. Whereas ventilation with high tidal volumes directly decreases Na,K-adenosintriphosphatase activity,45 ventilation at low lung volumes may indirectly impair fluid clearance due to hypoxia following increased alveolar collapse.46
Impairment of barrier function of the endothelium and epithelium, as well as of fluid clearance leads to the development of interstitial and alveolar oedema, which subsequently causes surfactant dysfunction, and impairs lungs elastic and resistive properties.47 Dysfunction of the surfactant system makes the lung susceptible to alveolar collapse contributing to deterioration of lung mechanics and impairing pulmonary host defense.48
Although most evidence of gross structural alterations of endothelium and epithelium induced by mechanical ventilation originates from in vitro investigations of cultured cells or in vivo investigations in acute lung injury models,49 ventilation applying clinically relevant settings in non-injured lungs can affect the alveolar-capillary barrier function, especially in the presence of independent inflammatory triggers, making mechanical ventilation a powerful hit in presence of systemic inflammation.27
Due to the disturbed integrity of the alveolar-capillary barrier function and consecutive systemic translocation of pathogens or inflammatory mediators, VILI may lead to a systemic inflammatory response affecting not only the lungs, but distal organs as well.50
Lung inhomogeneity, e.g. due to atelectasis formation, is a major contributing factor to the development of VILI. However, most experimental evidence is derived from acute lung injury models. Although their basic pathogenic mechanisms may be similar, the magnitude and time course of atelectasis formation in acute lung injury may be very different from those of atelectasis occurring during anesthesia and relatively short-term intraoperative mechanical ventilation. Resorption of alveolar gas51,52 and compression of lung structures53-56 may lead to atelectasis during short-term mechanical ventilation in non-injured lungs, whereby the former might play a more important role.
In a porcine model of experimental pneumonia, both exogenous surfactant administration and ventilation according to the open lung approach attenuated bacterial growth and systemic translocation by minimizing alveolar collapse and atelectasis formation.57 In a similar model of experimental pneumonia in mechanically ventilated piglets, bacterial translocation was lowest with individually tailored PEEP levels, whereas low and high PEEP promoted bacterial translocation.58
In isolated non-perfused mouse lungs, both an “open lung approach” (tidal volume 6 mL/kg, recruitment manoeuvres and PEEP of 14 - 16 cmH2O) as well as a “lung rest strategy” (tidal volume of 6 ml/kg, PEEP of 8 - 10 cmH2O, no recruitment manoeuvres) were associated with reduced pulmonary inflammatory response and improved respiratory mechanics compared to injurious mechanical ventilation (tidal volume of 20 ml/kg, PEEP of 0 cmH2O).59 Interestingly, the “lung rest strategy” was associated with less apoptosis but more ultrastructural cell damage, most likely due to increased activation of mitogen-activated protein kinase pathways as compared to the “open lung strategy”.59
50
In healthy mice, mechanical ventilation with a tidal volume of 8 ml/kg and PEEP of 4 cmH2O induced a reversible increase in plasma and lung tissue cytokines as well as increased leukocyte influx, but the integrity of the lung tissue was preserved.60 In another investigation, even least-injurious ventilator settings were able to induce VILI in the absence of a previous pulmonary insult in mice.61 Of note, the deleterious effects of mechanical ventilation in non-injured lungs are partly dependent on its duration.62 However, an experimental study demonstrated that large tidal volumes had only minor if any deleterious effects on lungs, despite prolonged mechanical ventilation.23 Possibly, this is explained by the lack of a previous inflammatory insult, as for example surgery. In fact, systemic inflammation may prime the lungs to injury by mechanical ventilation.63
Mechanical ventilation strategies to protect lungs during surgeryAtelectasis and intraoperative mechanical ventilationAtelectasis develops in as much as 90% of patients undergoing general anesthesia,64 and can persist to different degrees after surgery, also surrounding pleura effusion, as illustrated in figure 2. The area of non-aerated lung tissue near to the diaphragm varies depending on the surgical procedure and patient characteristics, but has been estimated in the range of 3-6 %65-67 to 20-25%,64 and even higher if calculated as amount of tissue.
Different mechanisms have been postulated to favour atelectasis formation during anesthesia, including: 1) collapse of small airways;68-70 2) compression of lung structures;53-56 3) absorption
Figure 2. Magnetic resonance imaging (MRI) scans of lungs of three patients before and on the first day after open abdominal surgery
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of intra-alveolar gas content;51,52 and 4) impairment of lung surfactant function.71 Mechanical ventilation strategies for general anesthesia have been importantly influenced by the progressive decrease in oxygenation and compliance.72 Tidal volumes up to 15 mL/kg of predicted body weight were advocated to increase the end-expiratory lung volume (EELV) and counteract atelectasis in the intraoperative period.72 Provided there is no contraindication, PEEP and lung recruitment manoeuvres may also contribute to revert or prevent the loss of EELV and closure of small airways during anesthesia.
Tidal volumes for intraoperative protective ventilationDriven by clinical and experimental studies, tidal volumes during mechanical ventilation have been importantly reduced in patients suffering from the acute respiratory distress syndrome (ARDS) in order to limit lung overdistension.73 Influenced by this practice in intensive care unit patients, a similar trend was observed in the operation room. As reported by different investigators,74,75 average tidal volumes in the range of 6 to 9 mL/kg of predicted body weight have gained broad acceptance for non-injured lungs, in spite of experimental23,76 and clinical data77-
79 suggest that higher values are not associated with increased lung damage or inflammation. Furthermore, anaesthesiologists have consistently reduced tidal volumes also during one-lung ventilation. Whereas values as high as 10 mL/kg have been used in the past, experimental80,81 and clinical82-85 studies have suggested that tidal volumes of approximately 4 to 5 mL/kg may be more appropriate for lung protection, while still allowing adequate gas exchange. Furthermore, a small RCT showed that atelectasis did not increase significantly with low tidal volume without PEEP from induction of anesthesia until the end of surgery.65 This is also supported by the fact that mechanical ventilation with low tidal volume and PEEP did not result in a progressive deterioration of the respiratory system compliance and gas exchange during open abdominal surgery in a larger RCT.86 It must be kept in mind that “set” and “actual” (i.e. delivered) tidal volumes can differ substantially,87 and that settings should be adjusted judiciously.
Positive end-expiratory pressure for intraoperative protective ventilationClinical studies have shown that a PEEP of 10 cmH2O is required to reduce or eliminate atelectasis,67,88,89 improve compliance without increasing deadspace,90,91 and maintain end-expiratory lung volume during general anesthesia in both non-obese and obese patients.92 Another study in normal subjects showed that PEEP of 10 cmH2O increased lung volume, but did not improve the respiratory function compared to PEEP of 0 cmH2O.54 Certainly, the level of PEEP should be chosen according to the patient’s particular characteristics, the particularities of the surgical approach, and patient positioning. Several targets have been proposed for a more individual titration of PEEP during general anesthesia, including the following: 1) oxygenation,93 also combined with dead space,90 or EELV91 ; 2) mechanical properties of the respiratory system94 ; and 3) distribution of ventilation using electric impedance tomography.95,96 However, none of these has been shown to improve patient outcome.
Although controversial, an alternative approach for PEEP during general anesthesia is the so-called “intraoperative permissive atelectasis”, when PEEP is kept relatively low and recruitment manoeuvres are waived. This concept aims at reducing the static stress in lungs, which is closely related to the mean airway pressure, assuming that collapsed lung tissue is protected against injury from mechanical ventilation (figure 3). Intraoperative permissive atelectasis may be limited
52
Figure 3. Effects of high and low tidal volumes (VT) at end-inspiration and end-expiration with low and high PEEP during general anesthesia
by deterioration in oxygenation, which could require higher inspiratory oxygen fractions. Also, shear stress may occur at the interface between collapsed and open tissue,18 likely resulting in lung damage and inflammation, even in presence of low global stress.97 Theoretically, intraoperative low PEEP could increase the incidence and the amount of atelectasis even in the postoperative period, resulting in further PPCs. A recent large retrospective study investigating the association between intraoperative mechanical ventilator settings and outcomes suggested that the use of “minimal” PEEP (2.2 to 5 cmH2O) combined with low tidal volumes (6 to 8 mL/kg) is associated with increased risk of 30-day mortality.77 However, a large international multicenter RCT challenged the concept that “minimal” PEEP combined with low tidal volumes in the intraoperative period is harmful.86 Also in elderly patients undergoing major open abdominal surgery, a strategy consisting of low tidal volume, PEEP 12 cmH2O and recruitment manoeuvres increased the PaO2 intraoperatively compared to a strategy with high tidal volume without PEEP, but this effect was not maintained in the postoperative period.98 Even without recruitment manoeuvres PEEP improved oxygenation during upper abdominal surgery compared to zero end-expiratory pressure, but again such effects were limited to the intraoperative period and did not prevent postoperative complications.99
Lung recruitment manoeuvres for intraoperative protective ventilationPEEP is most effective for preserving respiratory function if preceded by a recruitment manoeuvre, which must overcome the opening pressures of up to 40 cmH2O in non-obese,100 and 40-50 cmH2O in obese patients,101 in the absence of lung injury. Recruitment manoeuvres can be performed in different ways using the anesthesia ventilator, as illustrated in figure 4.
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Most commonly, such manoeuvres are performed by “bag squeezing” using the airway pressure-limiting valve of the anesthesia machine (figure 4A). However, recruitment manoeuvres are better controlled if performed during tidal ventilation, for example using a stepwise increase of PEEP, tidal volumes, or a combination of these (figure 4B). Provided there are no contraindications, the inspiratory plateau pressure as high as 40 cmH2O, are more likely to result in full recruitment.102
In anesthesia devices that allow pressure-controlled ventilation, recruitment manoeuvres can be conducted with a constant driving pressure of 15-20 cmH2O, and by increasing PEEP up to 20 cmH2O in steps of 5 cmH2O (30 to 60 s per step). After three to five breaths at a PEEP level that allows achieving the target inspiratory pressure, PEEP and tidal volume are adjusted to the respective desired levels (figure 4C).
A
B
C
Figure 4. Illustrative fluctuation of airway pressure during three types of lung recruitment manoeuvres for intraoperative mechanical ventilation
54
Tabl
e 3.
Ran
dom
ized
con
trol
led
tria
ls u
sing
non
clin
ical
prim
ary
outc
omes
Refe
renc
e/Ye
ar
publ
ishe
dSt
udy
desi
gnPa
tient
po
pula
tion/
N
umbe
rIn
terv
entio
n gr
oup(
s)Co
ntro
l gro
upN
oncl
inic
al p
rimar
y ou
tcom
esSe
cond
ary
outc
omes
Thor
acic
sur
gery
Wrig
ge e
t al.
2004
78
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
m
ajor
thor
acic
su
rger
yn=
34 (2
ex
clud
ed)
PV V T: 6
mL/
kgPE
EP: 1
0 cm
H 2O
P aw
Lim
it 35
cm
H 2O
durin
g TL
V an
d O
LVn=
15
CV V T: 1
2-15
mL/
kgZE
EPP a
w L
imit
35 c
mH 2
Odu
ring
TLV
and
OLV
n=17
Infla
mm
ator
y m
edia
tors
in
pla
sma:
no
diffe
renc
es
betw
een
grou
ps fo
r TN
Fα, I
L-1,
IL
-6, I
L-8,
IL-1
0, IL
-12
Gas
exc
hang
e: n
o di
ffere
nces
bet
wee
n gr
oups
Schi
lling
et a
l. 20
05 82
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
el
ectiv
e op
en
thor
acic
surg
ery
n=32
PV V T: 5
mL/
kgdu
ring
TLV
and
OLV
PEEP
: 3 c
mH 2
O, T
LVPE
EP: 0
-2 c
mH 2
O, O
LVP a
w L
imit
30 c
mH 2
On=
16
CV V T: 1
0 m
L/kg
durin
g TL
V an
d O
LVPE
EP: 3
cm
H 2O
, TLV
PEEP
: 0-2
cm
H 2O
, OLV
P aw
Lim
it 30
cm
H 2O
n=16
Infla
mm
ator
y m
edia
tors
in
BAL:
TN
Fα a
nd sI
CAM
low
er d
urin
g PV N
o di
ffere
nces
bet
wee
n gr
oups
fo
r cel
l cou
nt, P
MN
ela
stas
e,
tota
l pro
tein
, alb
umin
, IL-
8,
IL-1
0
PaO
2/FI
O2:
no
diffe
renc
es b
etw
een
grou
psPa
CO2:
high
er d
urin
g PV
Mic
hele
t et a
l. 20
06 83
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
pl
anne
d es
opha
gect
omy
n=52
PV V T: 9
mL/
kg, T
LVV T
: 5 m
L/kg
OLV
PEEP
: 5 c
mH 2
O, T
LV
and
OLV
n=26
CV V T: 9
mL/
kg, T
LV a
nd O
LVZE
EP, T
LV a
nd O
LV
n=26
Infla
mm
ator
y m
edia
tors
in
plas
ma:
IL-1
ß, IL
-6, I
L-8
low
er
durin
g PV
No
diffe
renc
es b
etw
een
grou
ps
for T
NFα
PaO
2/FI
O2
and
PaCO
2: hi
gher
dur
ing
PVEV
LWI:
low
er d
urin
g PV
Tim
e to
ext
ubati
on:
shor
ter d
urin
g PV
Lin
et a
l. 20
08 10
3
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
es
opha
gect
omy
n=40
PV V T: 1
0 m
L/kg
, TLV
V T: 5
-6 m
L/kg
OLV
PEEP
: 3-5
cm
H 2O
, OLV
n=20
CV V T: 1
0 m
L/kg
, TLV
and
OLV
ZEEP
, TLV
and
OLV
n=20
Infla
mm
ator
y m
edia
tors
in
plas
ma:
IL-6
, IL-
8, lo
wer
dur
ing
PV
P pea
k, P p
lat,
and
R aw
: lo
wer
dur
ing
PV
Review intraoperative protective ventilation
Chap
ter
3
55
Unz
ueta
et a
l. 20
12 10
4
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
el
ectiv
e op
en
thor
acot
omy
n=40
PV V T: 8
mL/
kg, T
LVV T
: 6 m
L/kg
OLV
PEEP
: 8 c
mH 2
O, T
LV
and
OLV
RM w
ith st
epw
ise
PEEP
/ Paw
incr
ease
un
til 2
0/40
cm
H 2O
be
fore
star
t of O
LVn=
20
CV V T: 8
mL/
kg, T
LVV T
: 6 m
L/kg
OLV
PEEP
: 8 c
mH 2
O, T
LV a
nd
OLV
no R
M b
efor
e st
art o
f OLV
n=20
Dead
spac
e: lo
wer
dur
ing
PVPa
O2/
FIO
2: hi
gher
du
ring
PVPa
CO2:
low
er d
urin
g PV
Card
iac
surg
ery
Kone
r et a
l. 20
04 10
5
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
el
ectiv
e on
-pum
p co
rona
ry a
rter
y by
pass
gra
fting
su
rger
yn=
44
(1) P
VV T
: 6 m
L/kg
PEEP
: 5 c
mH 2
On=
15(2
) CV+
PEEP
V T: 1
0 m
L/kg
PEEP
: 5 c
mH 2
On=
14
(3) C
V+ZE
EPV T
: 10
mL/
kgPE
EP: 0
cm
H 2O
n=15
Infla
mm
ator
y m
edia
tors
in
pla
sma:
no
diffe
renc
es
betw
een
grou
ps fo
r TN
Fα a
nd
IL-6
P pla
t: lo
wer
dur
ing
PV
com
pare
d to
bot
h CV
gr
oups
Shun
t fra
ction
: low
er
durin
g PV
com
pare
d to
bo
th C
V+ZE
EPPa
O2/
FIO
2: hi
gher
du
ring
venti
latio
n w
ith
PEEP
, (1)
+ (2
)
Zupa
ncic
h et
al.
2005
106
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
el
ectiv
e on
-pum
p co
rona
ry a
rter
y by
pass
gra
fting
su
rger
yn=
40
PV V T: 8
mL/
kgPE
EP: 1
0 cm
H 2O
n=20
CV V T: 1
0-12
mL/
kgPE
EP: 2
-3 c
mH 2
On=
20
Infla
mm
ator
y m
edia
tors
in
plas
ma
and
BAL:
IL-6
, IL-
8,
low
er d
urin
g PV
in b
oth.
PaCO
2: hi
gher
dur
ing
PV
Reis
Mira
nda
et
al. 2
005
93
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
el
ectiv
e on
-pum
p co
rona
ry a
rter
y by
pass
gra
fting
or
val
ve su
rger
yn=
62
(1) L
ate
open
lung
V T: 4
-6 m
L/kg
PEEP
: 10
cmH 2
Ost
artin
g at
pos
top
ICU
ar
rival
n=18
(2) E
arly
ope
n lu
ngV T
: 4-6
mL/
kgPE
EP: 1
0 cm
H 2O
star
ting
after
in
tuba
tion
n=22
(3) V
T: 6-
8 m
L/kg
PEEP
: 5 c
mH 2
On=
22
Infla
mm
ator
y m
edia
tors
in
plas
ma:
IL-8
dec
reas
ed a
fter
CPB
in b
oth
open
lung
gro
ups;
IL
-10
decr
ease
d fa
ster
afte
r CP
B in
ear
ly o
pen
lung
gro
up
Evid
ence
of
perio
pera
tive
myo
card
ial i
nfar
ction
(c
k-M
B an
d EC
G):
no
diffe
renc
es b
etw
een
grou
ps
56
Abdo
min
al s
urge
ry
Wrig
ge e
t al.
2004
78
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
m
ajor
abd
omin
al
surg
ery
n=30
PV V T: 6
mL/
kgPE
EP: 1
0 cm
H 2O
P aw
Lim
it 35
cm
H 2O
n=15
CV V T: 1
2-15
mL/
kgZE
EPP a
w L
imit
35 c
mH 2
On=
15
Infla
mm
ator
y m
edia
tors
in
pla
sma:
no
diffe
renc
es
betw
een
grou
ps fo
r TN
Fα, I
L-1,
IL
-6, I
L-8,
IL-1
0, IL
-12
PaO
2/FI
O2:
no
diffe
renc
es b
etw
een
grou
psPa
CO2:
high
er d
urin
g PV
Wol
thui
s et a
l. 20
08 10
7
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
a
surg
ical
pr
oced
ure
in g
ener
al
anes
thes
ia ≥
5hn=
46
PV V T: 6
mL/
kgPE
EP: 1
0 cm
H 2O
n=24
CV V T: 1
0-12
mL/
kgZE
EPn=
22
Infla
mm
ator
y m
edia
tors
in
pla
sma
and
BAL:
low
er
mye
lope
roxi
dase
and
nu
cleo
som
e le
vel i
n BA
L du
ring
PV
PaCO
2: hi
gher
dur
ing
PVPP
Cs: n
o di
ffere
nces
be
twee
n gr
oups
Wei
ngar
ten
et
al. 2
010
98
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
ag
ed >
65y
unde
rgoi
ng
maj
or o
pen
abdo
min
al
surg
ery
unde
r ge
nera
l an
esth
esia
n=40
PV V T: 6
mL/
kgPE
EP: 1
2 cm
H 2O
RM w
ith st
epw
ise
PEEP
incr
ease
unti
l 15
cmH 2
On=
20
CV V T: 1
0 m
L/kg
ZEEP
no R
Mn=
20
Infla
mm
ator
y m
edia
tors
in
pla
sma:
no
diffe
renc
es
betw
een
grou
ps
PaO
2/FI
O2 +
PaC
O2:
high
er d
urin
g PV
Com
plia
nce
high
er a
nd
resis
tanc
e lo
wer
dur
ing
PV
Spin
al s
urge
ry
Mem
tsou
dis
et
al. 2
012
108
Pros
pecti
ve,
singl
e-ce
ntre
, ra
ndom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
el
ectiv
e lu
mba
r de
com
pres
sion
and
fusio
n in
pr
one
positi
on
unde
r gen
eral
an
esth
esia
n=26
PV V T: 6
mL/
kgPE
EP: 8
cm
H 2O
n=13
CV V T: 1
2 m
L/kg
ZEEP
n=13
Infla
mm
ator
y m
edia
tors
in
pla
sma:
no
diffe
renc
es
betw
een
grou
psPa
CO2:
high
er d
urin
g PV
BAL,
bro
ncho
alve
olar
lava
ge; C
K-M
B, m
uscl
e-br
ain
type
cre
atine
kin
ase;
CPB
, car
diop
ulm
onar
y by
pass
; CV,
con
venti
onal
ven
tilati
on; E
CG, e
lect
roca
rdio
gram
; EVL
WI,
extr
avas
cula
r lun
g w
ater
inde
x; F
IO2,
insp
ired
fracti
on o
f oxy
gen;
ICAM
, int
erce
llula
r adh
esio
n m
olec
ule;
ICU,
inte
nsiv
e ca
re u
nit;
IL, i
nter
leuk
in; P
aw, a
irway
pre
ssur
e; P
peak
. pea
k pr
essu
re; P
plat
, pla
teau
pre
ssur
e;
PaCO
2, pa
rtial
pre
ssur
e of
art
eria
l car
bon
diox
ide;
PaO
2, pa
rtial
pre
ssur
e of
art
eria
l oxy
gen;
PaO
2/FI
O2,
ratio
of p
artia
l pre
ssur
e of
art
eria
l oxy
gen
to in
spire
d fra
ction
of o
xyge
n; P
EEP,
positi
ve
end–
expi
rato
ry p
ress
ure;
PM
N, p
olym
orph
onuc
lear
leuk
ocyt
e; P
PCs,
post
oper
ative
pul
mon
ary
com
plica
tions
; PV,
pro
tecti
ve ve
ntila
tion;
OLV
, one
-lung
venti
latio
n; R
aw, a
irway
resis
tanc
e; R
M,
recr
uitm
ent m
anoe
uvre
; sIC
AM, s
olub
le in
terc
ellu
lar a
dhes
ion
mol
ecul
e; T
NFα,
tum
our n
ecro
sis fa
ctor
alp
ha; T
LV, t
wo-
lung
ven
tilati
on; V
T, tid
al v
olum
e; Z
EEP,
zero
end
–exp
irato
ry p
ress
ure
Review intraoperative protective ventilation
Chap
ter
3
57
Recent evidence for intraoperative protective ventilation Randomized controlled trials using non-clinical primary outcomesThe literature search identified eleven RCTs that compared a protective ventilation strategy with a non-protective ventilation strategy during general anesthesia for surgery with regard to non-clinical primary outcome in patients undergoing thoracic surgery,78,82,83,103,104 cardiac surgery,93,105,106 abdominal surgery,78,98,107 or spinal surgery,108 as depicted in table 3. In eight RCTs the protective ventilation strategy consisted of both lower tidal volumes and higher levels of PEEP;78,83,98,103,105-108 in two RCTs, it consisted of either lower tidal volume,82 a higher level of PEEP.93 In one RCT, lung recruitment manoeuvres were used during the protective ventilation strategy.104
The effects on inflammatory responses are slightly contradictory. While four RCTs showed no difference in local levels of inflammatory mediators between patients on protective and those on non-protective ventilation,78,98,105,108 six RCTs showed that protective strategies were associated with lower levels of inflammatory mediators.82,83,93,103,106,107
Randomized controlled trials using clinical primary outcomesIn total, 8 RCTs were identified that compared a protective ventilation strategy with a non-protective ventilation strategy during surgery with regard to a clinical primary outcomes in patients planned for abdominal surgery,86,109-111 thoracic surgery,85,112 cardiac surgery,113 or spinal surgery,114 as shown in table 4. In four RCTs the protective strategy consisted of both lower tidal volumes and higher levels of PEEP,110-112,114 in the four remaining RCTs it consisted of either lower tidal volumes,85,109,113 or higher levels of PEEP.86
Four trials reported on PPCs in the first postoperative days, including bronchitis, hypoxemia, and atelectasis,114 pneumonia, need for invasive or non-invasive ventilation for acute respiratory failure,110 a modified “Clinical Pulmonary Infection Score” and chest x–ray abnormalities,111 and hypoxemia, bronchospasm, suspected pulmonary infection, pulmonary infiltrate, aspiration pneumonitis, development of ARDS, atelectasis, pleural effusion, pulmonary oedema, and pneumothorax.86
In a Chinese single-centre RCT,114 investigators compared protective ventilation (tidal volume 6 mL/kg and 10 cmH2O PEEP) versus non-protective (tidal volume 10 to 12 mL/kg and 0 cmH2O PEEP) in 60 elderly American Society of Anesthesiologists class II and III patients scheduled for spinal surgery. Patients receiving protective ventilation had less PPCs.
In a French multi-centre trial (Intraoperative PROtective VEntilation, IMPROVE),110 protective ventilation (tidal volume 6 to 8 mL/kg and PEEP 6 to 8 cmH2O) was compared with non-protective ventilation (tidal volume 10 to 12 mL/kg and 0 cmH2O PEEP in 400 non-obese patients at intermediate to high risk of pulmonary complications after planned major abdominal surgery. The primary outcome (postoperative pulmonary and extra–pulmonary complications) occurred less often in patients receiving ‘protective’ ventilation. Such complications have been ascribed to the release of inflammatory mediators by the lungs into the systemic circulation, affecting the lungs,115 as well as peripheral organs.50 These patients also had a shorter length of hospital stay, but mortality was unaffected.
58
Tabl
e 4.
Ran
dom
ized
con
trol
led
tria
ls u
sing
clin
ical
prim
ary
outc
omes
Refe
renc
e/Ye
ar p
ublis
hed
Stud
y de
sign
Patie
nt p
opul
ation
/ N
umbe
rIn
terv
entio
nCo
ntro
l gro
upCl
inic
al p
rimar
y ou
tcom
esSe
cond
ary
outc
omes
Thor
acic
sur
gery
Mas
low
et.
al.
2013
112
Pros
pecti
ve, s
ingl
e-ce
ntre
, ran
dom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
ele
ctive
pulm
onar
y re
secti
on=3
4
PV V T: 5
mL/
kg, T
LV a
nd
OLV
PEEP
: 5 c
mH 2
O, T
LV
and
OLV
n=17
CV V T: 1
0 m
L/kg
, TLV
an
d O
LVZE
EP, T
LV a
nd O
LVn=
17
Rate
of a
tele
ctas
is:
low
er w
ith C
V;le
ngth
of h
ospi
tal
stay
: no
diffe
renc
es
betw
een
grou
ps
PaCO
2 abd
dea
d sp
ace:
hig
her
durin
g PV
C dyn
: hig
her d
urin
g CV
Shen
et a
l. 20
13 85
Pros
pecti
ve, s
ingl
e-ce
ntre
, ran
dom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
ele
ctive
th
orac
osco
pic
esop
hage
ctom
yn=
101
PV V T: 8
mL/
kg, T
LVV T
: 5 m
L/kg
OLV
PEEP
: 5 c
mH 2
O, T
LV
and
OLV
n=53
CV V T: 8
mL/
kg, T
LVV T
: 8 m
L/kg
OLV
ZEEP
, TLV
and
OLV
n=48
PPCs
: low
er ra
te
with
PV
Mor
talit
y: n
o di
ffere
nce
betw
een
grou
ps
PaO
2/FI
O2
and
PaCO
2: hi
gher
du
ring
PVIn
flam
mat
ory
med
iato
rs in
BA
L: lo
wer
IL-1
ß, IL
-6 a
nd IL
-8
Card
iac
surg
ery
Sund
ar e
t al.
2011
11
3
Pros
pecti
ve, s
ingl
e-ce
ntre
, ran
dom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
ele
ctive
ca
rdia
c su
rger
yn=
149
PV V T: 6
mL/
kgPE
EP/F
IO2:
acco
rdin
g to
ARD
S N
etw
ork
tabl
en=
75
CV V T: 1
0 m
L/kg
PEEP
/FIO
2: ac
cord
ing
to
ARDS
Net
wor
k ta
ble
n=74
Rate
of r
eint
ubati
on:
low
er w
ith P
VN
umbe
r of p
atien
ts
requ
iring
ven
tilati
on
6h p
osto
pera
tivel
y:
low
er w
ith P
V
Gas
exc
hang
e: n
o di
ffere
nce
betw
een
grou
ps
Abdo
min
al s
urge
ry
Tres
chan
et a
l. 20
12 10
9
Pros
pecti
ve, s
ingl
e-ce
ntre
, ran
dom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
ele
ctive
up
per a
bdom
inal
surg
ery
≥3 h
und
er c
ombi
ned
gene
ral a
nd e
pidu
ral
anes
thes
ian=
101
PV V T: 6
mL/
kgPE
EP: 5
cm
H 2O
n=50
CV V T: 1
2 m
L/kg
PEEP
: 5 c
mH 2
On=
51
Rate
of a
tele
ctas
is:
low
er w
ith C
V
PaO
2/FI
O2:
high
er d
urin
g CV
C dyn
and
Raw
: hig
her d
urin
g CV
PaO
2 at p
osto
pera
tive
day
5:
high
er w
ith C
V
Review intraoperative protective ventilation
Chap
ter
3
59
Futie
r et a
l. 20
13
110
Pros
pecti
ve
rand
omize
d co
ntro
lled
mul
ti-ce
ntre
stud
y
Adul
ts p
atien
ts a
t in
term
edia
te to
hig
h ris
k of
pul
mon
ary
com
plic
ation
s un
derg
oing
maj
or
abdo
min
alsu
rger
yn=
400
PV V T: 6
-8 m
L/kg
PEEP
: 6-8
cm
H 2O
n=20
0
CV V T: 1
0-12
mL/
kgZE
EPn=
200
Com
posit
e pr
imar
y ou
tcom
e of
maj
or
pulm
onar
y or
ex
trap
ulm
onar
y co
mpl
icati
ons:
low
er
with
PV
Redu
ced
rate
of a
tele
ctas
is,
pneu
mon
ia, n
eed
for
venti
latio
n w
ithin
7 d
ays a
nd
seps
is w
ith P
V.Re
duce
d le
ngth
of h
ospi
tal
stay
with
PV
Seve
rgni
ni e
t al.
2013
111
Pros
pecti
ve, s
ingl
e-ce
ntre
, ran
dom
ized
cont
rolle
d tr
ial
Adul
t pati
ents
un
derg
oing
ele
ctive
op
en a
bdom
inal
surg
ery
≥2 h
n=56
(1 e
xclu
ded)
PV V T: 7
mL/
kgPE
EP: 1
0 cm
H 2O
n=28
CV V T: 9
mL/
kgZE
EPn=
27
Pulm
onar
y fu
nctio
n te
sts:
impr
oved
with
PV
Mod
ified
Clin
ical
Pul
mon
ary
Infe
ction
Sco
re: l
ower
with
PV
PaO
2 at
pos
tope
rativ
e da
ys 1
, 3,
5: h
ighe
r with
PV
Rate
of c
hest
x-r
ay
abno
rmal
ities
: low
er w
ith P
VLe
ngth
of h
ospi
tal s
tay:
no
diffe
renc
e be
twee
n gr
oups
PRO
VE N
etw
ork
Inve
stiga
tors
20
14 86
Pros
pecti
ve,
inte
rnati
onal
, m
ultic
ente
r, ra
ndom
ized
cont
rolle
d tr
ial
Adul
ts p
atien
ts a
t in
term
edia
te to
hig
h ris
k of
pul
mon
ary
com
plic
ation
s un
derg
oing
maj
or
abdo
min
alsu
rger
yn=
900
PV V T: 8
mL/
kgPE
EP: 1
2 cm
H 2O
RM w
ith st
epw
ise
incr
ease
of V
T afte
r in
ducti
on a
nd b
efor
e ex
tuba
tion
n=44
5
CV V T: 8
mL/
kgPE
EP: 0
-2 c
mH 2
On=
449
Rate
of P
PCs:
no
diffe
renc
e be
twee
n gr
oups
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Review intraoperative protective ventilation
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An Italian single–centre trial111 investigated the effectiveness of protective ventilation (tidal volume 7 mL/kg and 10 cmH2O PEEP with recruitment manoeuvres) versus non–protective ventilation (tidal volume 9 mL/kg and zero end-expiratory pressure) in 56 patients scheduled for open abdominal surgery lasting more than 2 hours. The modified “Clinical Pulmonary Infection Score” was lower in patients receiving protective ventilation. These patients also had fewer chest x–ray abnormalities and higher arterial oxygenation compared to patients receiving non-protective ventilation.
Finally, in an international multicenter trial conducted in Europe and the Americas (PROtective Ventilation using HIgh versus LOw PEEP, PROVHILO),86 the PROtective VEntilation (PROVE) Network–investigators compared PEEP of 12 cmH2O combined with recruitment manoeuvres versus PEEP of 2 cmH2O without recruitment manoeuvres in 900 non-obese patients at high risk for postoperative pulmonary complications planned for open abdominal surgery under ventilation at tidal volumes of 8 mL/kg. The incidence of PPCs was not different between patients receiving protective ventilation and patients receiving non-protective ventilation.
Challenges of studies using bundles As shown in preceding subsections “Randomized controlled trials using non-clinical primary outcomes” and “Randomized controlled trials using clinical primary outcomes”, most RCTs addressing intraoperative mechanical ventilation compared bundles of interventions consisting of tidal volumes and levels of PEEP, usually accompanied by a lung recruitment maneuver.110-112,114 Notably, recruitment manoeuvres differed between the trials. In the Italian single-centre RCT,111 investigators used incremental titration of tidal volumes until a plateau pressure of 30 cmH2O, directly after induction of anesthesia, after any disconnection from the ventilator and immediately before extubation, similar as in PROVHILO.86 In IMPROVE,110 recruitment was performed with a continuous positive airway pressure of 30 cmH2O for 30 seconds every 30 minutes, also known as sustained inflation, after tracheal intubation. Finally, in the Chinese single-centre RCT,114 the recruitment manoeuvres followed a similar approach, but to plateau pressures of up to 35 cmH2O, and they were performed every 15 minutes. It is difficult, if not impossible to conclude from these trials what caused the benefit: tidal volume reduction or increase of PEEP, or both, and to determine the role of recruitment manoeuvres. Moreover, to what extent the recruitment manoeuvre has succeeded in reopening lung has not been analysed in the different studies.
The results of the PROVHILO trial, however, suggest that low tidal volumes rather than PEEP combined with lung recruitment manoeuvres are responsible for lung protection in the intraoperative period. This interpretation is also supported by an analysis of different studies on the odds ratios of lower tidal volumes,85,109,113 higher levels of PEEP,86 as well as their combination,110-112,114 regarding the development of PPCs (figure 5).
Certainly, these conclusions are only valid for the studied population, that is, non-obese patients at risk of PPCs undergoing elective abdominal surgery. Other patient populations could still benefit from higher levels of PEEP and recruitment manoeuvres.
Challenges of composite outcome measuresComposite outcome measures offer the benefit of an increased event rate, which is helpful
62
to ensure adequate statistical power of a trial.8 It is reasonable to combine related outcomes that represent different aspects of a single underlying pathophysiological process, like PPCs for VILI. There are, though, two major limitations regarding the use of composite outcomes. First, the component variables can differ importantly in terms of severity and frequency. Second, differences in the frequency of component variables in a composite outcome may be masked.
Drawbacks of protective ventilationThe term “protective” in the context of mechanical ventilation implies a decrease in the major components of VILI, namely atelectrauma, volutrauma and biotrauma. However, a strategy that is protective to lungs may also cause harm to other organ systems. The potential for harm caused by protective ventilation was reported in PROVHILO,86 in which patients receiving higher PEEP and lung recruitment manoeuvres developed intraoperative hypotension more frequently and needed more vasoactive drugs. These findings are at least in part in line with the finding that protective ventilation was associated with a higher incidence of intraoperative hypotension in the French trial.110
Figure 6. Settings of VT (Panel A) and PEEP (Panel B) according to observational studies of mechanical ventilation in the operation room; and settings of VT (Panel C) and PEEP (Panel D) in “non–protective” ventilation (red) and “protective” ventilation (blue) groups
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Standard of care versus unusual settings: Were the control groups of recent trials representative of clinical practice? In RCTs addressing intraoperative protective mechanical ventilation, the strategy used to treat control groups can play an important role when drawing conclusions for daily practice of general anesthesia. Metaanalyses suggest that lower tidal volumes are protective not only during long-term ventilation in critically ill patients,116,117 but also short-term ventilation during general anesthesia for surgery.117 Accordingly, anaesthesiologists have been using tidal volumes of approximately 8 to 9 mL/kg on average, and seldom higher than 10 mL/kg,74 as also illustrated in figure 6A. In contrast to this practice, the tidal volumes used in the control groups of recent RCTs were as high as 9111 to 12 mL/kg110, except to PROVHILO (figure 6B),86 which used a tidal volume of 7 mL/kg both in the intervention and in the control group. Similarly, levels of PEEP in the control arms of three out of four recent RCTs110,111,114 on protective mechanical ventilation were much lower than the standard of care at the moment the respective studies were designed (figure 6C and 6D). Taken together, these facts suggest that, among the most important recent RCTs on intraoperative protective mechanical ventilation, only the PROVHILO trial used a control group that reproduced the standard of anesthesia care at the time it was conducted. Accordingly, the PROVHILO trial addressed a major question regarding mechanical ventilation during anesthesia, namely whether the combination of high PEEP with recruitment manoeuvres confers protection against PPCs. In this study, high PEEP was not individualized, but based on previous findings from computed tomography67,88,89 and physiological studies.90,92
Intraoperative mechanical ventilation according to the utmost recent evidenceA number of reviews and commentaries have suggested that intraoperative mechanical ventilation for surgery should consist of low tidal volumes (6 to 8 mL/kg), moderate levels of PEEP (6 to 8 cmH2O), and periodic lung recruitment manoeuvres (e.g. every 30 min).5, 118-120 However, previous reviews and recommendations have been based on bundles, which do not permit to infer on the contribution of individual measures. Furthermore, the results of the largest RCT in this field (PROVHILO) could not be taken into account. Also, a recommendation regarding the use of positive pressure ventilation during induction and emergence of anesthesia, as proposed recently,119 is not supported by outcome data. Currently, the only recommendations that can be given for clinical practice are summarized in figure 7. In non-obese patients without ARDS121 undergoing open abdominal surgery, mechanical ventilation should be performed with low tidal volumes (approximately 6 to 8 mL/kg) combined with low PEEP (≤ 2 cmH2O), since higher PEEP combined with recruitment manoeuvres does not confer further protection against PPCs and can deteriorate the hemodynamics. If hypoxemia develops and provided that other causes have been excluded (e.g. hypotension, hypoventilation, pulmonary embolism etc.), the FiO2 should be increased first, followed by increase of PEEP, and recruitment manoeuvres based on stepwise increase of tidal volume during regular mechanical ventilation, according to the rescue algorithm described in the PROVHILO trial,86 provided no contra-indication is present. In patients with ARDS121 undergoing open abdominal surgery, intraoperative mechanical ventilation should be guided by the ARDS network protocol,122 whereby higher PEEP values123 may be useful in more
64
severe ARDS.124 If the target PaO2 (55 to 80 mmHg) or SpO2 (88 to 95%) cannot be achieved, a maximal lung recruitment manoeuvre with a decremental PEEP trial can be considered.125
Future perspectives
Despite the increasing number of highly qualitative RCTs on intraoperative mechanical ventilation, a number of issues remain unaddressed. While metaanalyses strongly suggest that low tidal volumes during intraoperative mechanical ventilation protect against postoperative pulmonary events, no single RCT has been able to prove this claim. Since metaanalyses in this field frequently include studies that tested intervention bundles, for example low tidal volume and high PEEP with recruitment manoeuvres versus high tidal volumes without PEEP, the estimation of the effects of single measures, for example low tidal volume or PEEP, is prone to criticism. Therefore, RCTs are most relevant for clinical practice if they test single interventions, and if control groups reproduce current standards. Whereas direct testing of the hypothesis that intraoperative low tidal volumes protect against PPCs is still lacking, ethical issues preclude such a trial.
Figure 7. Proposed settings of protective mechanical ventilation in non-obese patients during open abdominal surgery according to the concept of intraoperative permissive atelectasis
Review intraoperative protective ventilation
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Despite convincing evidence that PEEP and recruitment manoeuvres do not confer further protection, and may even impair hemodynamics during a ventilatory strategy based on low tidal volumes in open abdominal surgery, we do not know whether patients with obesity or undergoing one lung anesthesia procedures may benefit from those interventions. Also, we cannot rule out the possibility that an individual PEEP titration targeted on lung function could yield different results. Furthermore, it remains unclear how postoperative atelectasis, the most frequent of the different PPCs, influences the development of pulmonary infections, severe respiratory failure and affects other relevant outcome measures, including hospital length of stay and mortality. In addition, further studies should shed light on the potential contributions of ventilatory strategies during induction and emergence of anesthesia, as well as in the postoperative period (e.g. non-invasive ventilation). Accordingly, the potential of perioperative non-ventilatory measures (e.g. muscle paralysis, use of short-acting neuromuscular blocking agents as well as monitoring and reversal of muscle paralysis, early mobilization, and respiratory therapy etc.) for reducing PPCs should be investigated. Such studies are necessary to support future guidelines on the practice of perioperative mechanical ventilation and adjunctive measures in a broad spectrum of patients as well as surgical interventions, both open and laparoscopic.
Conclusions
The potential of intraoperative lung protective mechanical ventilation to reduce the incidence of PPCs is well established. RCTs have suggested that low tidal volumes, high PEEP and recruitment manoeuvres may be protective intraoperatively, but the precise role of each single intervention has been less clearly defined. A metaanalysis taking the utmost recent clinical data shows that the use of low tidal volumes, rather than PEEP, recruitment manoeuvres, or a combination of these two, is the most important determinant of protection in intraoperative mechanical ventilation. In non-obese patients without ARDS undergoing open abdominal surgery, mechanical ventilation should be performed with low tidal volumes (approximately 6 to 8 mL/kg) combined with low PEEP, since the use of higher PEEP combined with recruitment manoeuvres does not confer further protection against PPCs and can deteriorate the hemodynamics. If hypoxemia develops, and provided that other causes have been excluded, for example, hypotension, hypoventilation, pulmonary embolism etc., the FiO2 should be increased first, followed by increase of PEEP, and recruitment manoeuvres based on stepwise increase of tidal volume during regular mechanical ventilation. Further studies are warranted to guide intraoperative mechanical ventilation in a broader spectrum of patients and surgical interventions.
66
Figure LegendsFigure 1. Alterations of the extracellular matrix in lungs during mechanical ventilation and fluid administration. CS-PG, condroitin sulphate proteoglycans; HS-PG, heparan sulphate proteoglycans; ICs, inflammatory cells; IMs, inflammatory mediators; MMPs, metalloproteases; MV, mechanical ventilation; Pi, interstitial pressure; SB, spontaneous breathing; W/D, wet/dry ratio.
Figure 2. Magnetic resonance imaging (MRI) scans of lungs of three patients before and on the first day after open abdominal surgery. Images were obtained throughout spontaneous breathing and represent an average of total lung volume (TLV) during the breath cycles. Panel A – minor atelectasis; Panel B – major atelectasis; Panel C – pleural effusion. Segmentation of lungs, atelectasis (red lines) and pleura effusion (blue lines) in MRI scans was performed manually. Values were calculated for whole lungs. Note that the amounts of atelectasis and pleura effusion, two common postoperative pulmonary complications are relatively low after surgery. L, left side of chest; MRI, magnetic resonance imaging; PreOP, preoperative; PostOP, postoperative, R, right side of chest; TLV, total lung volume.
Figure 3. Effects of high and low tidal volumes (VT) at end-inspiration and end-expiration with low and high PEEP during general anesthesia. Atelectatic lung regions (red), overinflated lung regions (blue), normally aerated lung regions (white). During ventilation with low tidal volume and low PEEP, higher amounts of atelectasis are present at end-expiration and end-inspiration with minimal areas of overinflation; During ventilation with high tidal volume and low PEEP, less atelectasis is present at end-expiration and end inspiration, with increased areas of overinflation at end-inspiration. Furthermore, a higher amount of tissue collapsing and de-collapsing during breathing is present. During ventilation with low tidal volume and higher PEEP, less atelectasis is present. However, higher overinflation occurs at end- inspiration and end-expiration, with minimal collapse and reopening during breathing cycling. PEEP, positive end-expiratory pressure; VT, tidal volume.
Figure 4. Illustrative fluctuation of airway pressure during three types of lung recruitment manoeuvres for intraoperative mechanical ventilation (red lines); Panel A, “Bag squeezing” using the airway pressure-limiting valve of the anesthesia machine. The airway pressure is difficult to control, possibly resulting in overpressure, with the risk of barotrauma, or values lower than the closing pressure of small airways when controlled mechanical ventilation is resumed, with consequent lung derecruitment; Panel B, “Stepwise increase of tidal volume” during volume-controlled ventilation. PEEP is set at 12 cmH2O, the respiratory frequency at 6 to 8 breaths/min, and tidal volume increased from 8 mL/kg in steps of 4 mL/kg until the target opening pressure (e.g. 30-40 cmH2O) is achieved. After three to five breaths at that pressure, the PEEP is kept at 12 cmH2O, tidal volume reduced to 6 to 8 mL/kg, and the respiratory frequency adjusted to normocapnia; Panel C, Stepwise increase of PEEP at a constant driving pressure of 15 to 20 cmH2O in pressure-controlled ventilation. The PEEP is increased in steps of 5 cmH2O (30 to 60 s per step) up to 20 cmH2O. After three to five breaths at a PEEP level that allows achieving the target inspiratory pressure, PEEP and tidal volume are adjusted to the respective desired levels. PEEP, positive end-expiratory pressure.
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Figure 5. Odds ratios for postoperative pulmonary complications of “protective” versus “non-protective” ventilation in trials comparing different tidal volumes,85,109,113 different tidal volumes and positive end-expiratory pressure (PEEP),110-112,114 and different levels of PEEP.86
Figure 6. Settings of VT (Panel A) and PEEP (Panel B) according to observational studies of mechanical ventilation in the operation room (in Canada,128 France,129 and the USA3,74,75,130); settings of VT (Panel C) and PEEP (Panel D) in “non–protective” ventilation (red) and “protective” ventilation (blue) groups in four recent randomized controlled trials (Severgnini et al.,111 IMPROVE,110 Ge et al.,114 and PROVHILO86). PBW, predicted body weight; PEEP, positive end-expiratory pressure; VT, tidal volume.
Figure 7. Proposed settings of protective mechanical ventilation in non-obese patients during open abdominal surgery according to the concept of intraoperative permissive atelectasis. ARDS, acute respiratory distress syndrome; FIO2, inspiratory oxygen fraction of oxygen; PBW, predicted body weight; PEEP, positive end-expiratory pressure; Pplat, inspiratory airway plateau pressure; SpO2, peripheral oxygen saturation; RR, respiratory rate; VT, tidal volume.
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58. Lachmann RA, van Kaam AH, Haitsma JJ, Lachmann B: High positive end-expiratory pressure levels promote bacterial translocation in experimental pneumonia. Intensive Care Med 2007; 33: 1800-4
59. Fanelli V, Mascia L, Puntorieri V, Assenzio B, Elia V, Fornaro G, Martin EL, Bosco M, Delsedime L, Fiore T, Grasso S, Ranieri VM: Pulmonary atelectasis during low stretch ventilation: “Open lung” versus “lung rest” strategy. Crit Care Med 2009; 37: 1046-53
60. Vaneker M, Halbertsma FJ, van Egmond J, Netea MG, Dijkman HB, Snijdelaar DG, Joosten LA, van der Hoeven JG, Scheffer GJ: Mechanical ventilation in healthy mice induces reversible pulmonary and systemic cytokine elevation with preserved alveolar integrity: An in vivo model using clinical relevant ventilation settings. Anesthesiology 2007; 107: 419-26
61. Wolthuis EK, Vlaar AP, Choi G, Roelofs JJ, Juffermans NP, Schultz MJ: Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice. Crit Care 2009; 13: R1
62. Hegeman MA, Hemmes SN, Kuipers MT, Bos LD, Jongsma G, Roelofs JJ, van der Sluijs KF, Juffermans NP, Vroom MB, Schultz MJ: The extent of ventilator-induced lung injury in mice partly depends on duration of mechanical ventilation. Crit Care Res Pract 2013; 2013: 435236
63. Wellman TJ, Winkler T, Costa EL, Musch G, Harris RS, Zheng H, Venegas JG, Vidal Melo MF: Effect of local tidal lung strain on inflammation in normal and lipopolysaccharide-exposed sheep*. Crit Care Med 2014; 42: e491-500
64. Lundquist H, Hedenstierna G, Strandberg A, Tokics L, Brismar B: CT-assessment of dependent lung densities in man during general anaesthesia. Acta Radiol 1995; 36: 626-32
65. Cai H, Gong H, Zhang L, Wang Y, Tian Y: Effect of low tidal volume ventilation on atelectasis in patients during general anesthesia: A computed tomographic scan. J Clin Anesth 2007; 19: 125-9
66. Rusca M, Proietti S, Schnyder P, Frascarolo P, Hedenstierna G, Spahn DR, Magnusson L: Prevention of atelectasis formation during induction of general anesthesia. Anesth Analg 2003; 97: 1835-9
67. Neumann P, Rothen HU, Berglund JE, Valtysson J, Magnusson A, Hedenstierna G: Positive end-expiratory pressure prevents atelectasis during general anaesthesia even in the presence of a high inspired oxygen concentration. Acta Anaesthesiol Scand 1999; 43: 295-301
44: 238-4470. Bergman NA, Tien YK: Contribution of the closure of pulmonary units to impaired oxygenation during anesthesia.
Anesthesiology 1983; 59: 395-40171. Stanley TH, Zikria BA, Sullivan SF: The surface tension of tracheobronchial secretions during general anesthesia.
Anesthesiology 1972; 37: 445-972. Bendixen HH, Hedley-Whyte J, Laver MB: Impaired Oxygenation in Surgical Patients during General Anesthesia with
Controlled Ventilation: A Concept of Atelectasis. NEJM 1963; 269: 991-673. Esteban A, Frutos-Vivar F, Muriel A, Ferguson ND, Penuelas O, Abraira V, Raymondos K, Rios F, Nin N, Apezteguia C,
Violi DA, Thille AW, Brochard L, Gonzalez M, Villagomez AJ, Hurtado J, Davies AR, Du B, Maggiore SM, Pelosi P, Soto L, Tomicic V, D’Empaire G, Matamis D, Abroug F, Moreno RP, Soares MA, Arabi Y, Sandi F, Jibaja M, Amin P, Koh Y, Kuiper MA, Bulow HH, Zeggwagh AA, Anzueto A: Evolution of mortality over time in patients receiving mechanical ventilation.
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Am J Respir Crit Care Med 2013; 188: 220-3074. Hess DR, Kondili D, Burns E, Bittner EA, Schmidt UH: A 5-year observational study of lung-protective ventilation in the
operating room: A single-center experience. J Crit Care 2013; 28: 533 e9-1575. Levin MA, McCormick PJ, Lin HM, Hosseinian L, Fischer GW: Low intraoperative tidal volume ventilation with minimal
PEEP is associated with increased mortality. Br J Anaesth 2014; 113: 97-10876. Hong CM, Xu DZ, Lu Q, Cheng Y, Pisarenko V, Doucet D, Brown M, Aisner S, Zhang C, Deitch EA, Delphin E: Low
tidal volume and high positive end-expiratory pressure mechanical ventilation results in increased inflammation and ventilator-associated lung injury in normal lungs. Anesth Analg 2010; 110: 1652-60
77. Wrigge H, Zinserling J, Stuber F, von Spiegel T, Hering R, Wetegrove S, Hoeft A, Putensen C: Effects of mechanical ventilation on release of cytokines into systemic circulation in patients with normal pulmonary function. Anesthesiology 2000; 93: 1413-7
78. Wrigge H, Uhlig U, Zinserling J, Behrends-Callsen E, Ottersbach G, Fischer M, Uhlig S, Putensen C: The effects of different ventilatory settings on pulmonary and systemic inflammatory responses during major surgery. Anesth Analg 2004; 98: 775-81,
79. Wrigge H, Uhlig U, Baumgarten G, Menzenbach J, Zinserling J, Ernst M, Dromann D, Welz A, Uhlig S, Putensen C: Mechanical ventilation strategies and inflammatory responses to cardiac surgery: A prospective randomized clinical trial. Intensive Care Med 2005; 31: 1379-87
80. Gama de Abreu M, Heintz M, Heller AR, Sezchenyi RCM, Albrecht DM, Koch T: One-lung ventilation with high tidal volumes and zero positive end-expiratory pressure is injurious in the isolated rabbit lung model. Anesth Analg 2003; 96: 220-8
81. Kozian A, Schilling T, Schutze H, Senturk M, Hachenberg T, Hedenstierna G: Ventilatory protective strategies during thoracic surgery: Effects of alveolar recruitment maneuver and low-tidal volume ventilation on lung density distribution. Anesthesiology 2011; 114: 1025-35
82. Schilling T, Kozian A, Huth C, Buhling F, Kretzschmar M, Welte T, Hachenberg T: The pulmonary immune effects of mechanical ventilation in patients undergoing thoracic surgery. Anesth Analg 2005; 101: 957-65,
83. Michelet P, D’Journo XB, Roch A, Doddoli C, Marin V, Papazian L, Decamps I, Bregeon F, Thomas P, Auffray JP: Protective ventilation influences systemic inflammation after esophagectomy: A randomized controlled study. Anesthesiology 2006; 105: 911-9
84. Licker M, Diaper J, Villiger Y, Spiliopoulos A, Licker V, Robert J, Tschopp JM: Impact of intraoperative lung-protective interventions in patients undergoing lung cancer surgery. Crit Care 2009; 13: R41
85. Shen Y, Zhong M, Wu W, Wang H, Feng M, Tan L, Wang Q: The impact of tidal volume on pulmonary complications following minimally invasive esophagectomy: A randomized and controlled study. J Thorac Cardiovasc Surg 2013; 146: 1267-73
86. Hemmes SN, Gama de Abreu M, Pelosi P, Schultz MJ: High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): A multicentre randomised controlled trial. Lancet 2014; 384: 495-503
87. Scott DH, Drummond GB: III. Tidal volume measurement: OK for science, but too difficult for a workstation standard? Br J Anaesth 2013; 110: 891-5
88. Brismar B, Hedenstierna G, Lundquist H, Strandberg A, Svensson L, Tokics L: Pulmonary densities during anesthesia with muscular relaxation: A proposal of atelectasis. Anesthesiology 1985; 62: 422-8
89. Reinius H, Jonsson L, Gustafsson S, Sundbom M, Duvernoy O, Pelosi P, Hedenstierna G, Freden F: Prevention of atelectasis in morbidly obese patients during general anesthesia and paralysis: A computerized tomography study. Anesthesiology 2009; 111: 979-87
90. Maisch S, Reissmann H, Fuellekrug B, Weismann D, Rutkowski T, Tusman G, Bohm SH: Compliance and dead space fraction indicate an optimal level of positive end-expiratory pressure after recruitment in anesthetized patients. Anesth Analg 2008; 106: 175-81
91. Satoh D, Kurosawa S, Kirino W, Wagatsuma T, Ejima Y, Yoshida A, Toyama H, Nagaya K: Impact of changes of positive end-expiratory pressure on functional residual capacity at low tidal volume ventilation during general anesthesia. J Anesth 2012; 26: 664-9
92. Futier E, Constantin JM, Petit A, Jung B, Kwiatkowski F, Duclos M, Jaber S, Bazin JE: Positive end-expiratory pressure improves end-expiratory lung volume but not oxygenation after induction of anaesthesia. Eur J Anaesthesiol 2010; 27: 508-13
93. Reis Miranda D, Gommers D, Struijs A, Dekker R, Mekel J, Feelders R, Lachmann B, Bogers AJ: Ventilation according to the open lung concept attenuates pulmonary inflammatory response in cardiac surgery. Eur J Cardiothorac Surg 2005; 28: 889-95
94. Cinnella G, Grasso S, Spadaro S, Rauseo M, Mirabella L, Salatto P, De Capraris A, Nappi L, Greco P, Dambrosio M: Effects of recruitment maneuver and positive end-expiratory pressure on respiratory mechanics and transpulmonary pressure during laparoscopic surgery. Anesthesiology 2013; 118: 114-22
95. Karsten J, Luepschen H, Grossherr M, Bruch HP, Leonhardt S, Gehring H, Meier T: Effect of PEEP on regional ventilation
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during laparoscopic surgery monitored by electrical impedance tomography. Acta Anaesthesiol Scand 2011; 55: 878-8696. Zhao Z, Guttmann J, Moller K: Adaptive SLICE method: An enhanced method to determine nonlinear dynamic respiratory
system mechanics. Physiol Meas 2012; 33: 51-6497. Gattinoni L, Carlesso E, Caironi P: Stress and strain within the lung. Curr Opin Crit Care 2012; 18: 42-798. Weingarten TN, Whalen FX, Warner DO, Gajic O, Schears GJ, Snyder MR, Schroeder DR, Sprung J: Comparison of two
ventilatory strategies in elderly patients undergoing major abdominal surgery. Br J Anaesth 2010; 104: 16-2299. Wetterslev J, Hansen EG, Roikjaer O, Kanstrup IL, Heslet L: Optimizing peroperative compliance with PEEP during
upper abdominal surgery: Effects on perioperative oxygenation and complications in patients without preoperative cardiopulmonary dysfunction. Eur J Anaesthesiol 2001; 18: 358-65
100. Rothen HU, Neumann P, Berglund JE, Valtysson J, Magnusson A, Hedenstierna G: Dynamics of re-expansion of atelectasis during general anaesthesia. Br J Anaesth 1999; 82: 551-6
101. Tusman G, Groisman I, Fiolo FE, Scandurra A, Arca JM, Krumrick G, Bohm SH, Sipmann FS: Noninvasive monitoring of lung recruitment maneuvers in morbidly obese patients: The role of pulse oximetry and volumetric capnography. Anesth Analg 2014; 118: 137-44
102. Rothen HU, Sporre B, Engberg G, Wegenius G, Hedenstierna G: Re-expansion of atelectasis during general anaesthesia: A computed tomography study. Br J Anaesth 1993; 71: 788-95
103. Lin WQ, Lu XY, Cao LH, Wen LL, Bai XH, Zhong ZJ: [Effects of the lung protective ventilatory strategy on proinflammatory cytokine release during one-lung ventilation]. Ai Zheng 2008; 27: 870-3
104. Unzueta C, Tusman G, Suarez-Sipmann F, Bohm S, Moral V: Alveolar recruitment improves ventilation during thoracic surgery: A randomized controlled trial. Br J Anaesth 2012; 108: 517-24
105. Koner O, Celebi S, Balci H, Cetin G, Karaoglu K, Cakar N: Effects of protective and conventional mechanical ventilation on pulmonary function and systemic cytokine release after cardiopulmonary bypass. Intensive Care Med 2004; 30: 620-6
106. Zupancich E, Paparella D, Turani F, Munch C, Rossi A, Massaccesi S, Ranieri VM: Mechanical ventilation affects inflammatory mediators in patients undergoing cardiopulmonary bypass for cardiac surgery: A randomized clinical trial. J Thorac Cardiovasc Surg 2005; 130: 378-83
107. Wolthuis EK, Choi G, Dessing MC, Bresser P, Lutter R, Dzoljic M, van der Poll T, Vroom MB, Hollmann M, Schultz MJ: Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents pulmonary inflammation in patients without preexisting lung injury. Anesthesiology 2008; 108: 46-54
108. Memtsoudis SG, Bombardieri AM, Ma Y, Girardi FP: The effect of low versus high tidal volume ventilation on inflammatory markers in healthy individuals undergoing posterior spine fusion in the prone position: A randomized controlled trial. J Clin Anesth 2012; 24: 263-9
109. Treschan TA, Kaisers W, Schaefer MS, Bastin B, Schmalz U, Wania V, Eisenberger CF, Saleh A, Weiss M, Schmitz A, Kienbaum P, Sessler DI, Pannen B, Beiderlinden M: Ventilation with low tidal volumes during upper abdominal surgery does not improve postoperative lung function. Br J Anaesth 2012; 109: 263-71
110. Futier E, Constantin JM, Paugam-Burtz C, Pascal J, Eurin M, Neuschwander A, Marret E, Beaussier M, Gutton C, Lefrant JY, Allaouchiche B, Verzilli D, Leone M, De Jong A, Bazin JE, Pereira B, Jaber S, Group IS: A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. NEJM 2013; 369: 428-37
111. Severgnini P, Selmo G, Lanza C, Chiesa A, Frigerio A, Bacuzzi A, Dionigi G, Novario R, Gregoretti C, de Abreu MG, Schultz MJ, Jaber S, Futier E, Chiaranda M, Pelosi P: Protective Mechanical Ventilation during General Anesthesia for Open Abdominal Surgery Improves Postoperative Pulmonary Function. Anesthesiology 2013: 1307-21
112. Maslow AD, Stafford TS, Davignon KR, Ng T: A randomized comparison of different ventilator strategies during thoracotomy for pulmonary resection. J Thorac Cardiovasc Surg 2013; 146: 38-44
113. Sundar S, Novack V, Jervis K, Bender SP, Lerner A, Panzica P, Mahmood F, Malhotra A, Talmor D: Influence of low tidal volume ventilation on time to extubation in cardiac surgical patients. Anesthesiology 2011; 114: 1102-10
114. Ge Y, Yuan L, Jiang X, Wang X, Xu R, Ma W: [Effect of lung protection mechanical ventilation on respiratory function in the elderly undergoing spinal fusion]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2013; 38: 81-5
115. Bouadma L, Dreyfuss D, Ricard JD, Martet G, Saumon G: Mechanical ventilation and hemorrhagic shock-resuscitation interact to increase inflammatory cytokine release in rats. Crit Care Med 2007; 35: 2601-6
116. Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P: Metaanalysis: Ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med 2009; 151: 566-76
117. Serpa Neto A, Cardoso SO, Manetta JA, Pereira VG, Esposito DC, Pasqualucci Mde O, Damasceno MC, Schultz MJ: Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: A metaanalysis. JAMA 2012; 308: 1651-9
118. Goldenberg NM, Steinberg BE, Lee WL, Wijeysundera DN, Kavanagh BP: Lung-protective ventilation in the operating room: Time to implement? Anesthesiology 2014; 121: 184-8
119. Futier E, Marret E, Jaber S: Perioperative positive pressure ventilation: An integrated approach to improve pulmonary care. Anesthesiology 2014; 121: 400-8
120. Coppola S, Froio S, Chiumello D: Protective lung ventilation during general anesthesia: Is there any evidence? Crit Care 2014; 18: 210
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121. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS: Acute respiratory distress syndrome: The Berlin Definition. JAMA 2012; 307: 2526-33
122. The Acute Respiratory Distress Syndrome N: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. NEJM 2000; 342: 1301-8
123. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT, National Heart L, Blood Institute ACTN: Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome NEJM 2004; 351: 327-36
124. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS, Pullenayegum E, Zhou Q, Cook D, Brochard L, Richard JC, Lamontagne F, Bhatnagar N, Stewart TE, Guyatt G: Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: Systematic review and metaanalysis. JAMA 2010; 303: 865-73
125. Borges JB, Okamoto VN, Matos GF, Caramez MP, Arantes PR, Barros F, Souza CE, Victorino JA, Kacmarek RM, Barbas CS, Carvalho CR, Amato MB: Reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 174: 268-78
126. Trillo-Alvarez C, Cartin-Ceba R, Kor DJ, Kojicic M, Kashyap R, Thakur S, Thakur L, Herasevich V, Malinchoc M, Gajic O: Acute lung injury prediction score: Derivation and validation in a population-based sample. Eur Respir J 2011; 37: 604-9
127. Kor DJ, Warner DO, Alsara A, Fernandez-Perez ER, Malinchoc M, Kashyap R, Li G, Gajic O: Derivation and Diagnostic Accuracy of the Surgical Lung Injury Prediction Model. Anesthesiology 2011; 115: 117-28
128. Lellouche F, Dionne S, Simard S, Bussières J, Dagenais F: High tidal volumes in mechanically ventilated patients increase organ dysfunction after cardiac surgery. Anesthesiology 2012; 116: 1072-82
129. Jaber S, Coisel Y, Chanques G, Futier E, Constantin JM, Michelet P, Beaussier M, Lefrant JY, Allaouchiche B, Capdevila X, Marret E: A multicentre observational study of intra-operative ventilatory management during general anaesthesia: Tidal volumes and relation to body weight. Anaesthesia 2012; 67: 999-1008
130. Chaiwat O, Vavilala MS, Philip S, Malakouti A, Neff MJ, Deem S, Treggiari MM, Wang J, Lang JD: Intraoperative adherence to a low tidal volume ventilation strategy in critically ill patients with pre-existing acute lung injury. J Crit Care 2011; 26: 144-51
Chapter 4
LAS VEGAS – Local Assessment of Ventilatory Management during General Anaesthesia for Surgery and its effects on Postoperative Pulmonary Complications: a prospective, observational, international, multicentre cohort study
Hemmes SNT, Gama de Abreu M, Pelosi P, Schultz MJ European Journal of Anaesthesiology 2013; 30(5):205-7
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Mechanical ventilation is frequently used as a supportive strategy in intensive care medicine and anaesthesiology despite its potential to aggravate or even initiate lung injury. Indeed, overdistension of non–dependent lung regions and repetitive opening and closing of dependent lung regions may cause mechanical stress and strain eventually worsening or causing lung damage.1,2 Critically ill patients with acute respiratory distress syndrome (ARDS) requiring long–term mechanical ventilation (i.e., for days) have been found to benefit from lung–protective mechanical ventilation settings that limit airway pressures and tidal volumes.3,4 Therefore, use of such lung–protective mechanical ventilation strategies is presently recommended in these patients.5 There is growing evidence that critically ill patients at risk for but not yet suffering from lung injury also benefit from pressure– and volume–limitation during long–term mechanical ventilation.6-8 While higher levels of positive end–expiratory pressure (PEEP) with or without recruitment manoeuvres during long–term mechanical ventilation benefits selected patients with ARDS, its use is not widely recommended.4 Evidence for beneficial effects of higher PEEP levels and recruitment manoeuvres during long–term mechanical ventilation in patients with uninjured lungs is lacking.
The effects of short–term mechanical ventilation (i.e., for hours) on pulmonary integrity are still to be defined.9 The potential benefits of lung–protective mechanical ventilation strategies during general anaesthesia for surgery in patients with uninjured lungs are even questioned.10 However, results from preclinical studies of short–term mechanical ventilation in animals without lung injury suggest possible beneficial effects of pressure– and tidal volume–limitations and the use of higher PEEP levels.2,11,12 In addition, intraoperative lung-protective mechanical ventilation may attenuate postoperative lung inflammation and prevent postoperative pulmonary complications.9,13 During short–term post–operative ventilation pressure– and tidal volume–limitation may also be protective.8,14,15 Although potentially beneficial, there is insufficient evidence whether the use of higher levels of PEEP during surgery prevents postoperative pulmonary complications.16
Consensus on optimal mechanical ventilation settings during general anaesthesia for surgery is largely lacking. Knowledge on intraoperative mechanical ventilation settings is very limited. One observational study, conducted in 49 centres in France, shows 18% of patients undergoing general anaesthesia for surgery to receive tidal volumes > 10 mL/kg predicted body weight during mechanical ventilation in the operation room. In addition, 81% received mechanical ventilation without PEEP.17 Information beyond this study are scarce, though some observational studies suggest poor use of pressure– and volume–limited mechanical ventilation during general anaesthesia for surgery.9,14,18 Thus, it is unclear how widespread the concept of lung–protective mechanical ventilation is applied in other countries.
Postoperative pulmonary complications are a major contributor to postoperative complications with a reported incidence varying from 2.6 to 5.0%.19,20 Postoperative pulmonary complications can be suggested to be dependent on intra–operative mechanical ventilation settings. Considering the high number of surgical procedures performed worldwide daily, estimated to be over 600.000, and the high incidence of complications (25%) and mortality (from 3.5 to 7%) in this patient population, even a small beneficial effect of lung–protective mechanical ventilation during general anaesthesia for surgery on postoperative pulmonary complications could have significant importance.21,22
LAS VEGAS study design
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The LAS VEGAS study aims at characterizing current mechanical ventilation practices during general anaesthesia for surgery and assessing the dependence of postoperative pulmonary complications on intraoperative mechanical ventilation settings. As secondary endpoints, we plan to assess intraoperative complications possibly related to mechanical ventilation settings, as well as the variation of applied mechanical ventilation settings within centres and between centres on an international basis.
This large observational study will provide valuable data, which can guide optimization of intraoperative mechanical ventilation to attenuate intraoperative and postoperative pulmonary complications. Prevention of ventilator-associated lung injury (VALI) could have substantial impact on postoperative pulmonary complications, postoperative clinical course and length of hospital stay.
The LAS VEGAS study is an international observational prospective non–interventional cohort study. It will include consecutive adult patients undergoing mechanical ventilation during general anaesthesia for surgery within a 7–day study period in the first months of 2013. Patients are followed during 5 postoperative days for postoperative pulmonary complications. At day 28 after surgery length of hospital stay and in hospital mortality are recorded. Patients undergoing obstetric surgical procedures or any procedure during pregnancy, surgical procedures outside the operating room, and surgical procedures involving extra–corporal circulation are excluded from participation. Two specific patient groups will be included in the study, but analysed separately: patients undergoing one–lung ventilation during surgery, and intensive care unit patients (i.e., patients who may have already received mechanical ventilation before the surgical procedure).
Patients will be recruited in both teaching and community centres worldwide. We aim to include a minimum of 4.800 patients in at least 96 centres. Taking into account an expected minimal incidence of 2.6% postoperative pulmonary complications, we anticipate that in order to provide a sample of 120 events inclusion of at least 4.800 patients is required. This will allow for inclusion of up to 12 covariates (including but not limited to mechanical ventilation settings, fluid loading, blood transfusion, ARISCAT risk score) in a logistic regression model to analyse the effect on post-operative pulmonary complications.20 For a logistic regression analysis the number of events divided by the number of predictor variables should be at least ten.23
The data to be collected are all collected as part of routine clinical care. Predefined risk factors for postoperative pulmonary complications (including, but not restricted to physical status, smoking status, chronic co-morbidity, transfusion of red blood cells, urgency of surgery, surgical procedure, fluid loading, use of epidural anaesthesia), intraoperative mechanical ventilation settings (ventilatory mode, airway pressures, tidal volume size, PEEP, respiratory rate), intraoperative complications possibly related to the mechanical ventilation strategy (oxygen desaturation, need for unplanned recruitment manoeuvres, need for pressure reduction, need for expiratory flow limitation, hypotension, need for vasoactive drugs, new arrhythmias) and postoperative pulmonary complications (new or prolonged invasive or non–invasive mechanical ventilation, need for oxygen therapy, respiratory failure, pneumonia, acute respiratory distress syndrome, pneumothorax) are recorded from the medical chart.19,20,24 In patients who are admitted to the intensive care unit after surgery a more detailed follow–up is performed. These patients will be part of an elective substudy, which can provide important information on post–operative critical care.
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All data is collected on paper case record forms, unless a local electronic system to register intraoperative and/or postoperative data is used (e.g., a patient data management system). All collected data are transcribed by local investigators into a web–based electronic Case Report Form (open source software OpenClinica).
In this multicenter study we will check for design effects. Design effects measures the effect of clustering due to multi–site recruitment of subjects. Student’s t–test or Mann-Whitney U–tests will be used to compare continuous variables and chi-squared tests for categorical variables. Comparison between and within groups will be performed using one–way ANOVA and post–hoc analyses for continuous variables. Study parameters of both patients receiving mechanical ventilation prior to operation and of patients undergoing one–lung ventilation during surgery will be analysed separately. Data from the intensive care unit sub–study will be analysed separately. To identify potential factors associated with intra– and post–operative pulmonary complications univariate analyses will be performed. A multivariate logistic regression model will be used to identify independent risk factors for post-operative pulmonary complications. To enter new terms into the model a stepwise approach will be used, with a limit of p < 0.05 to enter the terms. Time to event variables will be analysed using Cox regression and visualized by Kaplan–Meier curves. Statistical significance will be considered at p < 0.05.
All participating centres will submit the study protocol to their local Institutional Review Board for ethical judgment and obtain document of proof that the study has been subjected to ethical review and granted approval/favourable opinion. If required, ethical approval must be obtained before the start of inclusion.
The study is registered at Clinicaltrials.gov with registration identifier NCT 01601223.
The study will be performed by the LAS VEGAS collaboration on behalf of the European Society of Anaesthesiology (ESA). National coordinators will identify and recruit local participating centres, translate all study documents and ensure that all local necessary ethical and regulatory approvals are obtained before start of patient inclusion. They will assist, train and monitor local centres, ensuring conduction of the study according to the Good Clinical Practice guidelines of the International Conference on Harmonisation (ICH–GCP).25 Local coordinators in individual participating centres will provide scientific and structural leadership in their centre. They will guarantee the integrity of data collection and ensure timely completion of the dataset.
After publication of the primary results in a peer–reviewed medical journal, on request the pooled dataset will be available for all members of the LAS VEGAS collaboration for secondary analyses after judgment and approval of scientific quality and validity by the Steering Committee.
Funding
The study is funded by the European Society of Anaesthesiology (ESA) and supported by infrastructure provided by the Society.
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18. Blum JM, Maile M, Park PK, et al. A Description of Intraoperative Ventilator Management in Patients with Acute Lung Injury and the Use of Lung Protective Ventilation Strategies. Anesthesiology 2010; 115: 75-82
19. Smetana GW, Lawrence VA and Cornell JE. Preoperative pulmonary risk stratification for noncardiothoracic surgery: systematic review for the American College of Physicians. Annals of Internal Medicine 2006; 144: 581-595
20. Canet J, Gallart L, Gomar C, et al. Prediction of Postoperative Pulmonary Complications in a Population-based Surgical Cohort. Anesthesiology 2010; 113: 1338-1350
21. Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet 2008; 372: 139-144
22. Ghaferi AA, Birkmeyer JD and Dimick JB. Variation in hospital mortality associated with inpatient surgery. NEJM 2009; 361: 1368-1375
23. Bagley SC, White H and Golomb BA. Logistic regression in the medical literature: standards for use and reporting, with particular attention to one medical domain. Journal of clinical epidemiology 2001; 54: 979-985
24. Arozullah AM, Khuri SF, Henderson WG and Daley J. Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Annals of Internal Medicine 2001; 135: 847-857
25. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice. Journal of postgraduate medicine 2001; 47: 199-203
Chapter 5
Intraoperative Ventilation Strategies and Patient Outcomes Following Surgery: an International Observational Study (LAS VEGAS)
Hemmes SNT, Gama de Abreu M, Pelosi P, Schultz MJ for the The LAS VEGAS Investigators for PROVE Network*, and the Clinical Trial Network of the European Society of Anaesthesiology *PROVE Network: the PROtective VEntilation Network Manuscript submitted
82
Abstract
Background. Postoperative pulmonary complications (PPCs) increase morbidity and mortality of surgical patients. The intraoperative ventilation strategy may affect occurrence of PPCs.
Objective. To describe practice of intraoperative ventilation and to determine associations between ventilator settings and occurrence of PPCs.
Design, data source, setting and patients. Prospective observational study in adult patients requiring invasive ventilation during general anaesthesia for surgery in 2013.
Measurements. The primary outcome measure was development of PPCs in the first five postoperative days. A multivariable model was built to quantify the net effect of intraoperative ventilation characteristics on the occurrence of PPCs, while controlling for other perioperative risk factors.
Results. Data collection was complete in 8,241 patients (146 hospitals in 29 countries); PPCs occurred in 861 (10.4%) patients, arising most commonly within three days after surgery. Median tidal volume was 500.0 (454.2–550.5) mL resulting in 8.1 (7.2–9.1) mL/kg predicted body weight. The positive end–expiratory pressure (PEEP) level was 4.0 (0.0–5.0) cm H2O. PEEP levels of 0 and 5 cm H2O were used most frequently. Recruitment manoeuvres were performed in < 10% of patients. Increased levels of PEEP were independently associated with the occurrence of PPCs (odds ratio 1.06 (95% CI) 1.01–1.12; p = 0.020)).
Limitations. The observational character of this study precludes causal inferences.
Conclusion. Low tidal volumes are frequently used, but PEEP levels above 5 cm H2O and recruitment manoeuvres are seldom applied. Occurrence of PPCs is independently associated with the use of increasing intraoperative PEEP levels.
The study is registered at Clinicaltrials.gov, number NCT01601223.
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Introduction
Mechanical ventilation is often considered a harmless intervention during general anaesthesia for surgery. However, ventilation can induce overdistension as well as repetitive opening and closing of lung units, resulting in ventilator–induced lung injury and even the acute respiratory distress syndrome (ARDS).1 Several randomized controlled trials showed that ventilation with low tidal volumes (VT) is associated with improved outcome in patients with ARDS and in critically ill patients without ARDS,2–4 and this knowledge has profoundly changed ventilation practice in intensive care units.5–7
Theoretically, surgery patients with uninjured lungs could also benefit from intraoperative ventilation with low VT.3 Three randomized controlled trials in patients planned for major abdominal surgery showed that intraoperative ventilation with low VT and positive end–expiratory pressures (PEEP) with recruitment manoeuvres reduced occurrence of postoperative pulmonary complications (PPCs).8-10 One metaanalysis, however, suggested that VT, rather than PEEP, is the major factor responsible for lung protection during intraoperative ventilation.11 One recent multicentre audit in Australia showed that surgery patients remain to receive high VT (median 9.5 (8.5–10.4 mL/kg predicted body weight) and higher levels of PEEP (median 5.0 (4.0–5.0) cm H2O).12 Another study showed that the average size of VT during intraoperative ventilation is 7.8 ± 1.5 mL/kg predicted body weight, and that > 60% of patients receive ≥ 5 cm H2O of PEEP.13 Thus while there is controversy regarding VT, PEEP levels have increased, despite the fact that PEEP may not protect against PPC, and maybe even cause harm.11,14
We conducted the ‘Local ASsessment of VEntilatory management during General Anesthesia for Surgery, LAS VEGAS’ study, an international multicentre prospective observational study, to describe current intraoperative ventilation practice, and to determine associations between ventilator settings and patient outcome. We hypothesized that VT < 10 mL/kg PBW and PEEP levels ≥ 5 cm H2O were commonly used and both to be associated with a reduced occurrence of PPCs.
Methods
Study design and sites The LAS VEGAS study was co–sponsored and endorsed by the European Society of Anaesthesiology (ESA), which assisted in developing the electronic case record forms, and hosted the electronic database, without influencing study design, conduct, data analysis, and final reporting. The Writing Committee drafted the manuscript, and the Steering Committee provided revisions and comments. The study was registered at Clinicaltrials.gov (NCT01601223).
Study sites were recruited through the Clinical Trial Network of the ESA. Sites sought approval from the respective Institutional Review Board (research ethics committee), and if required, obtained written informed consent from individual patients. National coordinators assisted local coordinators and monitored the study according to the ‘International Conference on
84
Harmonization (Good Clinical Practice) guidelines.15 Local coordinators arranged regulatory approvals, monitored local researchers, and ensured integrity and timely completion of data collection.
Study population and data collectionAdult patients receiving invasive ventilation during general anaesthesia for elective or non–elective surgery were eligible for participation in the study, which ran for seven predefined days in each country, selected by the national coordinator, in the period between January 14th and March 4th, 2013. Patients were excluded from participation if they were aged < 18 years, or scheduled for pregnancy related surgery, surgical procedures outside the operating room, or procedures involving cardio-pulmonary bypass. Data from patients undergoing thoracic surgery or one–lung ventilation during surgery, and those who had received ventilation at any time in the previous 30 days were collected, but excluded from the present analysis. Centres performing more than 180 surgical procedures per week were allowed to randomly select either 25% or 50% of their eligible patients for inclusion (ALEA Version 2.2 | AMC/ALEA). The randomization procedure is described in the Supplement.
Baseline characteristics and preoperative risk factors for PPCs were identified from previous studies.16–19 During the intraoperative period we collected data describing ventilation settings and vital parameters hourly, and scored complications possibly related to ventilation, including episodes of hypoxia, use of recruitment manoeuvres, airway pressure reduction, presence of expiratory flow limitation, hypotension, use of vasoactive drugs, and new arrhythmias. Postoperative residual curarisation with neuromuscular blocking agents (NMBAs), defined as train–of–four stimulation (TOF) ratio < 0.9 was documented.
OutcomesThe following PPCs were scored daily from the day of surgery until hospital discharge or postoperative day 5: 1) need for supplementary oxygen (due to PaO2 < 60 mmHg or SpO2 < 90% in room air, excluding oxygen supplementation given as standard care or as continuation of preoperative therapy), 2) respiratory failure (PaO2 < 60 mmHg or SpO2 < 90% despite oxygen therapy, or need for non-invasive mechanical ventilation), 3) unplanned new or prolonged invasive or non–invasive mechanical ventilation, 4) acute respiratory distress syndrome, 5) pneumonia, and 6) pneumothorax. Length of hospital stay and in–hospital mortality was censored at postoperative day 28. Definitions of intraoperative complications, possible types of recruitment manoeuvres, and postoperative complications are provided in eTables 1, 2 and 3. Patient data were anonymized before entry onto a password secured, web–based electronic case record form (OpenClinica, Boston, MA, USA).
Statistical analysisSince the reported incidences of PPCs vary between 2.6% and 5.0%,16,17 we anticipated that to provide a sample of at least 120 PPC events, enrolment of 4,800 or more patients was required. This would allow up to 12 covariates in a logistic regression model for predicting PPCs.20
Part of the statistical analysis plan was published previously.21 Patients with incomplete data in main intraoperative ventilation settings including VT size (VT expressed in mL, and in mL/kg,
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PBW), PEEP and peak pressure level, or oxygen fraction in inspired air (FiO2) were censored. The ventilation settings were examined for plausibility and excluded if: VT < 100 or > 1500 mL, VT < 2 or > 20 mL/kg PBW, PEEP > 30 cm H2O, peak pressure < 5 or > 70 cm H2O, and FiO2 < 0.21 or > 1.0. The remaining cohort included only complete data of main ventilation settings and the primary endpoint.
Patient demographics, surgical characteristics, intraoperative characteristics, intraoperative complications, PPCs, length of hospital stay and in–hospital mortality are presented using descriptive statistics. Demographic data are presented as medians (with the 25 and 75% quartiles). Hourly–collected intraoperative variables were averaged per patient and are presented as medians (with the 25 and 75% quartiles). The occurrence of PPCs is presented as a collapsed composite of PPCs in the first five postoperative days. We calculated Kaplan-Meier estimates of survival curves, and we used log–rank tests to compare survival distributions in the overall cohort and also in the subgroups of BMI (< 35 vs. ≥ 35 kg/m2), ARISCAT (< 26 vs. ≥ 26) and laparoscopic vs. non–laparoscopic surgery. We considered PPC development as any PPC within five postoperative days, and within one patient. We censored data used for Kaplan–Meier estimates when patients did not have a PPC during the study period, or when patients were lost to follow–up before the end of postoperative day 5.
A multivariable model was built to quantify the association between intraoperative ventilation characteristics, including VT (expressed in mL/kg PBW), PEEP level, peak pressure, and FiO2, and the occurrence of PPCs, while controlling for other known preoperative and intraoperative risk factors for PPCs.15–18. We conducted multi–level analyses to adjust for clustering of the data. Therefore, generalized linear mixed model was used to determine predictors of PPC, by modelling PPC as the dependent variable over time. Independent variables were selected according to biologic plausibility, and when a p value less than 0.2 was found in the univariate analysis. Then, the generalized linear mixed model was conducted with these selected predictor variables as fixed effects, and centres where participants were treated (cluster) as a random effect. Effects were expressed as an average odds ratio (OR) with their respective 95% confidence interval (95% CI). The OR represents how the predictor affects outcome for the combined population of all clusters instead of one specific cluster. In the multivariable model statistical significance was set at a p value < 0.05.
Propensity scores for PPCs were estimated for each patient with logistic regression using 20 relevant baseline, intraoperative and postoperative characteristics (age, sex, BMI, ARISCAT,19 preoperative SpO2, functional status, smoking, chronic obstructive pulmonary disease (COPD), chronic comorbidity, respiratory infection < 30 days, preoperative anaemia, type of surgery, planned duration of surgery, condition of surgery, type of incision, fluid intake, epidural anaesthesia, use of and reversal of NMBAs, and postoperative residual curarisation) and correcting for the clustering of the data. The propensity score reflects the propensity in the range of 0 to 1 to present PPCs given a set of known variables, and is an attempt to adjust for potential selection bias, confounding factors, and differences between groups. Patients with missing data were excluded from the database. Based on the propensity score weighted estimators for the clustered data we constructed a propensity score–matched cohort. Matching was performed using nearest neighbour matching without replacement, with each patient with PPCs matched to
86
Figure 1. Data collection and selection of cohort for analysisIRB: institutional review board; VT: tidal volume; mL: millilitres; kg: kilogram; PBW: predicted body weight; PEEP: positive end-expiratory pressure; Ppeak: peak pressure; FiO2: inspired fraction of oxygen
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three patients without PPCs. A calibre width of 0.15 of the standard deviation of the logit of the propensity score was used for the development of matching. Absolute standardized differences were computed to evaluate matching effectiveness.22
A PROBIT regression analysis was used to characterize the dose–response relationship between the intraoperative PEEP level and the probability of PPCs. A cubic term was used in the final model for PEEP. The cubic term was chosen, because we hypothesized that the relationship between PEEP and PPCs is curvilinear with low probability in low levels, some plateau, and high probability in high levels. This was confirmed by the inspection of the residuals.
Post–hoc analyses were conducted for patients with body mass index (BMI) < versus ≥ 35 kg/m2, for patients undergoing laparoscopic versus non–laparoscopic surgery, and patients with low versus high risk for PPCs, according to the Assess Respiratory Risk in Surgical Patients in Catalonia risk (ARISCAT) score (< versus ≥ 26, respectively).19 The chi square test for categorical variables and Mann–Whitney U test for continuous variables were performed to compare the intraoperative ventilation strategies, intraoperative complications and PPCs within each subgroup. Statistical significance was considered to be at p < 0.05. All analyses were performed with R version 3.1 (http://www.R-project.org/).
Role of funding sourceThe European Society of Anaesthesiology supported LAS VEGAS. The funding sources had no role in study design, data analysis or interpretation, or writing of the manuscript.
Results
Two hundred and nineteen centres in 38 countries expressed interest in participating in the LAS VEGAS study. Of them, 73 in seven countries did not obtain formal approval from the local Institutional Review Board, or had other reasons not to participate (figure 1). One centre used the randomization program to reduce the number of patients to 50%, and another one to 25% of eligible patients. The list of participating centres, countries and respective numbers of included patients is presented in eTable 4; hospital characteristics of participating centres are given in eTable 5. In total 10,523 patients were recruited of whom 656 patients were excluded due to ventilation preceding surgery, or thoracic surgery, and 1,540 patients had missing data in main ventilation settings; in 86 patients the postoperative follow–up data was missed, yielding 8,241 patients for the analysis (figure 1). In the BMI subgroups an additional 18 patients were excluded due to missing weight and/or height. Of 7,594 patients follow–up was complete until the day of hospital discharge. Demographics and surgical characteristics of patients are shown in table 1 and eTable 6.
Intraoperative ventilation characteristicsAnaesthetists preferred volume– over pressure–controlled ventilation. The pressure support mode and combined modes of ventilation were seldom used (table 2). The most frequently chosen VT was 500 mL, or 7 to 9 mL/kg PBW, with limited variation (figure 2, table 2). VT was
88
lower than 8 and higher than 10 mL/kg PBW in 46% and 12% of patients, respectively (figure 2). The most frequently applied PEEP levels were 0 and 5 cm H2O (table 2, figure 2). PEEP levels were lower than 2, 2 to 5 and ≥ 6 cm H2O in 30%, 61%, and 9% of patients, respectively. Recruitment manoeuvres were applied in 9.5% of all patients.
Patient outcomesThe most frequent intraoperative complication was hypotension (table 3). PPCs occurred in 861 patients (10.4%), arising most commonly within three days after surgery (figure 3). The need for supplemental oxygen arose in 700 patients (8.5%), and 138 patients developed respiratory
Figure 2. Distribution of intraoperative ventilation settingsTidal volume size (expressed in mL and in mL/kg predicted body weight, PBW), level of PEEP (cm H2O), and peak pressure (cm H2O) presented for the whole group; patients with body mass index (BMI) lower than 35 kg/m2 versus equal or higher than 35 kg/m2; patients undergoing laparoscopic versus non–laparoscopic surgery; and patients with a low versus high risk for PPCs, according to the ARISCAT score (lower versus equal and higher than 26)
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failure (1.7%). ARDS, pneumonia, and pneumothorax occurred in less than 1% of patients (table 4). Patients who developed PPCs experienced a longer stay in hospital and greater mortality (eFigure 1 and 2).
The occurrence of PPCs was associated with increasing PEEP and peak pressure levels, and not associated with VT (table 5 and eTable 7). PPCs were also associated with patient age above 50 years, preoperative oxygen saturation ≤ 90%, current smoking, recent respiratory infection, and preoperative anaemia. PPCs were associated with the following surgery characteristics: urgent or emergency surgery, planned duration of surgery longer than two hours, abdominal incision, intraoperative events (fluid administration of 2,000 mL or more, hypoxemia, use of vasoactive drugs), postoperative residual curarisation, and no reversal of neuromuscular blockade (table 5 and eTable 7). The categorization of PEEP and tidal volume in tertiles did not change the results (eTable 8).
The characteristics of the propensity score matched cohort are show in eTable 9. Patients developing PPCs experienced more intraoperative complications, including hypoxemia, hypotension, arrhythmias, and need for vasoactive drugs (eTable 9). In the propensity score matched cohort, PEEP levels and peak pressure were associated with the development of PPCs (table 6).
Figure 4 and eFigure 4 respectively show the association between levels of PEEP and peak pressure with the occurrence of PPCs.
Post–hoc analysesIn patients with BMI ≥ 35 kg/m2, VT was higher (table 2, figure 2, eFigure 3). Also, FiO2, peak airway pressures and PEEP levels were higher (table 2) and recruitment manoeuvres more often used. The most frequent intraoperative complication was hypotension and need for vaso–active drugs, followed by de–saturation.
In laparoscopic vs. non–laparoscopic surgery, and in patients with ARISCAT scores19 ≥ 26 vs. < 26, VT sizes were comparable, but peak airway pressures as well as levels of PEEP were higher, and recruitment manoeuvres more frequently applied (table 3). FiO2 was higher in laparoscopic surgery, and lower in patients with ARISCAT ≥ 26.
The occurrence of PPCs was higher in patients with a BMI ≥ 35 kg/m2, and those with an ARISCAT score ≥ 26 (table 4).
In patients with BMI ≥ 35 kg/m2, higher PEEP levels and peak pressures were independently associated with the occurrence of PPCs (table 5). Also in patients with ARISCAT score ≥ 26, higher PEEP levels were independently associated with the occurrence of PPCs (table 5). Age > 50 years, urgent or emergency surgery, planned duration of surgery longer than two hours, intraoperative de–saturation, postoperative residual curarisation, and no reversal of neuromuscular blockade were consistently associated with PPCs (table 5 and eTables 10, 11, 12).
90
Tabl
e 1.
Dem
ogra
phic
s an
d su
rgic
al c
hara
cter
istic
s
Varia
ble
All p
atien
tsBM
I < 3
5BM
I ≥ 3
5N
on la
paro
scop
icLa
paro
scop
icAR
ISCA
T <
26AR
ISCA
T ≥
26
Mal
e se
x45
.0 (3
711/
8241
)46
.4 (4
020/
7507
)30
.4 (2
18/7
16)
47.6
(315
7/66
36)
34.5
(554
/160
5)43
.7 (2
664/
6097
)48
.8 (1
047/
2144
)
Age
(yea
rs)
54.0
(40.
0 –
66.0
)54
.0 (4
0.0
– 66
.0)
54.0
(43.
0 –
63.0
)54
.0 (4
1.0
– 67
.0)
50.0
(37.
0 –
63.0
)50
.0 (3
7.0
– 63
.0)
63.0
(51.
0 –
72.0
)
≤ 50
44.1
(363
5/82
39)
44.2
(332
1/75
06)
43.1
(308
/715
)42
.3 (2
806/
6634
)51
.7 (8
29/1
605)
51.5
(313
7/60
96)
23.2
(498
/214
3)
51 –
80
52.2
(430
4/82
39)
52.0
(390
3/75
06)
55.0
(393
/715
)53
.8 (3
571/
6634
)45
.7 (7
33/1
605)
46.7
(284
9/60
96)
67.9
(145
5/21
43)
> 80
3.6
(300
/823
9)3.
8 (2
82/7
506)
2.0
(14/
715)
3.9
(257
/663
4)2.
7 (4
3/16
05)
1.8
(110
/609
6)8.
9 (1
90/2
143)
BMI (
kg/m
2 )26
.2 (2
3.4
– 30
.0)
25.8
(23.
0 –
28.8
)38
.3 (3
6.2
– 41
.4)
26.1
(23.
3 –
29.7
)26
.9 (2
3.5
– 31
.2)
26.1
(23.
2 –
29.7
)26
.8 (2
3.7
– 30
.5)
Unde
rwei
ght (
< 18
.5)
2.4
(194
/822
3)2.
6 (1
94/7
507)
---2.
3 (1
51/6
623)
2.7
(43/
1600
)2.
3 (1
38/6
085)
2.6
(56/
2138
)
No o
besit
y (1
8.5
– 24
.9)
37.1
(305
1/82
23)
40.6
(305
1/75
07)
---37
.8 (2
506/
6623
)34
.1 (5
45/1
600)
38.6
(234
7/60
85)
32.9
(704
/213
8)
Ove
rwei
ght
(≥ 2
5.0
- 29.
9)35
.5 (2
917/
8223
)38
.9 (2
917/
7507
)---
36.2
(240
0/66
23)
32.3
(517
/160
0)35
.1 (2
133/
6085
)36
.7 (7
84/2
138)
Obe
sity
Clas
s 1
(30.
0 to
34.
9)16
.3 (1
345/
8223
)17
.9 (1
345/
7507
)---
16.0
(106
1/66
23)
17.8
(284
/160
0)16
.0 (9
76/6
085)
17.3
(369
/213
8)
Obe
sity
Clas
s 2
(35.
0 to
39.
9)5.
7 (4
64/8
223)
---64
.8 (4
64/7
16)
5.3
(351
/662
3)7.
1 (1
13/1
600)
5.4
(329
/608
5)6.
3 (1
35/2
138)
Mor
bid
obes
ity (≥
40)
3.1
(252
/822
3)---
35.2
(252
/716
)2.
3 (1
54/6
623)
6.1
(98/
1600
)2.
7 (1
62/6
085)
4.2
(90/
2138
)
ASA
phys
ical
stat
us c
lass
ifica
tion
syst
em
AS
A 1
29.5
(242
6/82
29)
31.5
(236
0/74
97)
8.7
(62/
714)
29.0
(192
1/66
29)
31.6
(505
/160
0)35
.8 (2
177/
6089
)11
.6 (2
49/2
140)
AS
A 2
49.2
(405
1/82
29)
48.5
(363
5/74
97)
57.6
(411
/714
)48
.5 (3
214/
6629
)52
.3 (8
37/1
600)
49.6
(301
9/60
89)
48.2
(103
2/21
40)
AS
A 3
19.6
(161
5/82
29)
18.5
(138
4/74
97)
31.5
(225
/714
)20
.5 (1
362/
6629
)15
.8 (2
53/1
600)
13.9
(844
/608
9)36
.0 (7
71/2
140)
AS
A 4
1.6
(134
/822
9)1.
5 (1
16/7
497)
2.1
(15/
714)
1.9
(129
/662
9)0.
3 (5
/160
0)0.
8 (4
7/60
89)
4.1
(87/
2140
)
AS
A 5
0.0
(3/8
229)
0.0
(2/7
497)
0.1
(1/7
14)
0.0
(3/6
629)
0.0
(0/1
600)
0.0
(2/6
089)
0.0
(1/2
140)
Func
tiona
l sta
tus
Non
dep
ende
nt93
.0 (7
662/
8237
)93
.2(6
994/
7503
)91
.3 (6
54/7
16)
92.3
(612
2/66
33)
96.0
(154
0/16
04)
94.8
(577
8/60
94)
87.9
(188
4/21
43)
Par
tially
dep
ende
nt5.
9 (4
83/8
237)
5.7
(428
/750
3)7.
3 (5
2/71
6)6.
5 (4
29/6
633)
3.4
(54/
1604
)4.
2 (2
58/6
094)
10.5
(225
/214
3)
Tot
ally
dep
ende
nt1.
1 (9
2/82
37)
1.1
(81/
7503
)1.
4 (1
0/71
6)1.
2 (8
2/66
33)
0.6
(10/
1604
)1.
0 (5
8/60
94)
1.6
(34/
2143
)
Bloo
d tr
ansf
usio
n (<
24h
pr
eope
rativ
ely)
0.
6 (5
2/82
41)
0.7
(49/
7507
)0.
4 (3
/716
)0.
7 (4
7/66
36)
0.3
(5/1
605)
0.1
(8/6
097)
2.1
(44/
2144
)
ARIS
CAT
scor
e$15
.0 (3
.0 –
26.
0)15
.0 (3
.0 –
26.
0)16
.0 (3
.0 –
27.
0)11
.0 (3
.0 –
23.
0)18
.0 (1
5.0
– 31
.0)
3.0
(0.0
– 1
6.0)
34.0
(30.
0 –
41.0
)
< 26
74.0
(609
7/82
41)
74.5
(559
4/75
07)
68.6
(491
/716
)76
.6 (5
084/
6636
)63
.1 (1
013/
1605
)10
0.0
(609
7/60
97)
---
26 –
44
21.8
(179
3/82
41)
21.3
(159
6/75
07)
26.7
(191
/716
)19
.3 (1
281/
6636
)31
.9 (5
12/1
605)
---83
.6 (1
793/
2144
)
> 44
4.3
(351
/824
1)4.
2 (3
17/7
507)
4.7
(34/
716)
4.1
(271
/663
6)5.
0 (8
0/16
05)
---16
.4 (3
51/2
144)
Preo
pera
tive
SpO
2 (%
)98
.0 (9
6.0
– 99
.0)
98.0
(96.
0 –
99.0
)97
.0 (9
5.0
– 98
.0)
98.0
(96.
0 –
99.0
)98
.0 (9
6.0
– 99
.0)
98.0
(97.
0 –
99.0
)97
.0 (9
5.0
– 98
.0)
≥ 96
83.6
(611
2/73
11)
84.5
(562
5/66
57)
74.4
(476
/640
)82
.8 (4
860/
5871
)86
.9 (1
252/
1440
)89
.9 (4
850/
5397
)65
.9 (1
262/
1914
)
91–9
515
.2 (1
114/
7311
)14
.4 (9
60/6
657)
23.6
(151
/640
)15
.9 (9
36/5
871)
12.4
(178
/144
0)10
.1 (5
47/5
397)
29.6
(567
/191
4)
≤ 9
01.
2 (8
5/73
11)
1.1
(72/
6657
)2.
0 (1
3/64
0)1.
3 (7
5/58
71)
0.7
(10/
1440
)0.
0 (0
/539
7)4.
4 (8
5/19
14)
Haem
oglo
bin
– g/
dL*
13.8
(12.
6 –
14.9
)13
.8 (1
2.6
– 14
.9)
13.8
(12.
8 –
14.9
)13
.8 (1
2.6
– 14
.9)
13.7
(12.
8 –
14.6
)13
.9 (1
2.9
– 15
.0)
13.3
(11.
6 –
14.5
)Pr
eope
rativ
e an
aem
ia
(Hb
≤ 10
g/d
l)3.
4 (2
38/6
929)
3.5
(224
/633
2)2.
2 (1
3/58
0)3.
7 (2
06/5
542)
2.3
(32/
1387
)1.
0 (5
0/49
27)
9.4
(188
/200
2)
LAS VEGAS study
Chap
ter
5
91
Tabl
e 1.
Dem
ogra
phic
s an
d su
rgic
al c
hara
cter
istic
s
Varia
ble
All p
atien
tsBM
I < 3
5BM
I ≥ 3
5N
on la
paro
scop
icLa
paro
scop
icAR
ISCA
T <
26AR
ISCA
T ≥
26
Mal
e se
x45
.0 (3
711/
8241
)46
.4 (4
020/
7507
)30
.4 (2
18/7
16)
47.6
(315
7/66
36)
34.5
(554
/160
5)43
.7 (2
664/
6097
)48
.8 (1
047/
2144
)
Age
(yea
rs)
54.0
(40.
0 –
66.0
)54
.0 (4
0.0
– 66
.0)
54.0
(43.
0 –
63.0
)54
.0 (4
1.0
– 67
.0)
50.0
(37.
0 –
63.0
)50
.0 (3
7.0
– 63
.0)
63.0
(51.
0 –
72.0
)
≤ 50
44.1
(363
5/82
39)
44.2
(332
1/75
06)
43.1
(308
/715
)42
.3 (2
806/
6634
)51
.7 (8
29/1
605)
51.5
(313
7/60
96)
23.2
(498
/214
3)
51 –
80
52.2
(430
4/82
39)
52.0
(390
3/75
06)
55.0
(393
/715
)53
.8 (3
571/
6634
)45
.7 (7
33/1
605)
46.7
(284
9/60
96)
67.9
(145
5/21
43)
> 80
3.6
(300
/823
9)3.
8 (2
82/7
506)
2.0
(14/
715)
3.9
(257
/663
4)2.
7 (4
3/16
05)
1.8
(110
/609
6)8.
9 (1
90/2
143)
BMI (
kg/m
2 )26
.2 (2
3.4
– 30
.0)
25.8
(23.
0 –
28.8
)38
.3 (3
6.2
– 41
.4)
26.1
(23.
3 –
29.7
)26
.9 (2
3.5
– 31
.2)
26.1
(23.
2 –
29.7
)26
.8 (2
3.7
– 30
.5)
Unde
rwei
ght (
< 18
.5)
2.4
(194
/822
3)2.
6 (1
94/7
507)
---2.
3 (1
51/6
623)
2.7
(43/
1600
)2.
3 (1
38/6
085)
2.6
(56/
2138
)
No o
besit
y (1
8.5
– 24
.9)
37.1
(305
1/82
23)
40.6
(305
1/75
07)
---37
.8 (2
506/
6623
)34
.1 (5
45/1
600)
38.6
(234
7/60
85)
32.9
(704
/213
8)
Ove
rwei
ght
(≥ 2
5.0
- 29.
9)35
.5 (2
917/
8223
)38
.9 (2
917/
7507
)---
36.2
(240
0/66
23)
32.3
(517
/160
0)35
.1 (2
133/
6085
)36
.7 (7
84/2
138)
Obe
sity
Clas
s 1
(30.
0 to
34.
9)16
.3 (1
345/
8223
)17
.9 (1
345/
7507
)---
16.0
(106
1/66
23)
17.8
(284
/160
0)16
.0 (9
76/6
085)
17.3
(369
/213
8)
Obe
sity
Clas
s 2
(35.
0 to
39.
9)5.
7 (4
64/8
223)
---64
.8 (4
64/7
16)
5.3
(351
/662
3)7.
1 (1
13/1
600)
5.4
(329
/608
5)6.
3 (1
35/2
138)
Mor
bid
obes
ity (≥
40)
3.1
(252
/822
3)---
35.2
(252
/716
)2.
3 (1
54/6
623)
6.1
(98/
1600
)2.
7 (1
62/6
085)
4.2
(90/
2138
)
ASA
phys
ical
stat
us c
lass
ifica
tion
syst
em
AS
A 1
29.5
(242
6/82
29)
31.5
(236
0/74
97)
8.7
(62/
714)
29.0
(192
1/66
29)
31.6
(505
/160
0)35
.8 (2
177/
6089
)11
.6 (2
49/2
140)
AS
A 2
49.2
(405
1/82
29)
48.5
(363
5/74
97)
57.6
(411
/714
)48
.5 (3
214/
6629
)52
.3 (8
37/1
600)
49.6
(301
9/60
89)
48.2
(103
2/21
40)
AS
A 3
19.6
(161
5/82
29)
18.5
(138
4/74
97)
31.5
(225
/714
)20
.5 (1
362/
6629
)15
.8 (2
53/1
600)
13.9
(844
/608
9)36
.0 (7
71/2
140)
AS
A 4
1.6
(134
/822
9)1.
5 (1
16/7
497)
2.1
(15/
714)
1.9
(129
/662
9)0.
3 (5
/160
0)0.
8 (4
7/60
89)
4.1
(87/
2140
)
AS
A 5
0.0
(3/8
229)
0.0
(2/7
497)
0.1
(1/7
14)
0.0
(3/6
629)
0.0
(0/1
600)
0.0
(2/6
089)
0.0
(1/2
140)
Func
tiona
l sta
tus
Non
dep
ende
nt93
.0 (7
662/
8237
)93
.2(6
994/
7503
)91
.3 (6
54/7
16)
92.3
(612
2/66
33)
96.0
(154
0/16
04)
94.8
(577
8/60
94)
87.9
(188
4/21
43)
Par
tially
dep
ende
nt5.
9 (4
83/8
237)
5.7
(428
/750
3)7.
3 (5
2/71
6)6.
5 (4
29/6
633)
3.4
(54/
1604
)4.
2 (2
58/6
094)
10.5
(225
/214
3)
Tot
ally
dep
ende
nt1.
1 (9
2/82
37)
1.1
(81/
7503
)1.
4 (1
0/71
6)1.
2 (8
2/66
33)
0.6
(10/
1604
)1.
0 (5
8/60
94)
1.6
(34/
2143
)
Bloo
d tr
ansf
usio
n (<
24h
pr
eope
rativ
ely)
0.
6 (5
2/82
41)
0.7
(49/
7507
)0.
4 (3
/716
)0.
7 (4
7/66
36)
0.3
(5/1
605)
0.1
(8/6
097)
2.1
(44/
2144
)
ARIS
CAT
scor
e$15
.0 (3
.0 –
26.
0)15
.0 (3
.0 –
26.
0)16
.0 (3
.0 –
27.
0)11
.0 (3
.0 –
23.
0)18
.0 (1
5.0
– 31
.0)
3.0
(0.0
– 1
6.0)
34.0
(30.
0 –
41.0
)
< 26
74.0
(609
7/82
41)
74.5
(559
4/75
07)
68.6
(491
/716
)76
.6 (5
084/
6636
)63
.1 (1
013/
1605
)10
0.0
(609
7/60
97)
---
26 –
44
21.8
(179
3/82
41)
21.3
(159
6/75
07)
26.7
(191
/716
)19
.3 (1
281/
6636
)31
.9 (5
12/1
605)
---83
.6 (1
793/
2144
)
> 44
4.3
(351
/824
1)4.
2 (3
17/7
507)
4.7
(34/
716)
4.1
(271
/663
6)5.
0 (8
0/16
05)
---16
.4 (3
51/2
144)
Preo
pera
tive
SpO
2 (%
)98
.0 (9
6.0
– 99
.0)
98.0
(96.
0 –
99.0
)97
.0 (9
5.0
– 98
.0)
98.0
(96.
0 –
99.0
)98
.0 (9
6.0
– 99
.0)
98.0
(97.
0 –
99.0
)97
.0 (9
5.0
– 98
.0)
≥ 96
83.6
(611
2/73
11)
84.5
(562
5/66
57)
74.4
(476
/640
)82
.8 (4
860/
5871
)86
.9 (1
252/
1440
)89
.9 (4
850/
5397
)65
.9 (1
262/
1914
)
91–9
515
.2 (1
114/
7311
)14
.4 (9
60/6
657)
23.6
(151
/640
)15
.9 (9
36/5
871)
12.4
(178
/144
0)10
.1 (5
47/5
397)
29.6
(567
/191
4)
≤ 9
01.
2 (8
5/73
11)
1.1
(72/
6657
)2.
0 (1
3/64
0)1.
3 (7
5/58
71)
0.7
(10/
1440
)0.
0 (0
/539
7)4.
4 (8
5/19
14)
Haem
oglo
bin
– g/
dL*
13.8
(12.
6 –
14.9
)13
.8 (1
2.6
– 14
.9)
13.8
(12.
8 –
14.9
)13
.8 (1
2.6
– 14
.9)
13.7
(12.
8 –
14.6
)13
.9 (1
2.9
– 15
.0)
13.3
(11.
6 –
14.5
)Pr
eope
rativ
e an
aem
ia
(Hb
≤ 10
g/d
l)3.
4 (2
38/6
929)
3.5
(224
/633
2)2.
2 (1
3/58
0)3.
7 (2
06/5
542)
2.3
(32/
1387
)1.
0 (5
0/49
27)
9.4
(188
/200
2)
92
Varia
ble
All p
atien
tsBM
I < 3
5 BM
I ≥ 3
5N
on la
paro
scop
icLa
paro
scop
icAR
ISCA
T <
26AR
ISCA
T ≥
26
Chro
nic
co-m
orbi
dity
- a
patie
nt ca
n ha
ve m
ore
than
one
co-m
orbi
dity
Met
asta
tic ca
ncer
4.1
(340
/824
1)4.
3 (3
24/7
507)
2.2
(16/
716)
4.4
(294
/663
6)2.
9 (4
6/16
05)
1.8
(111
/609
7)10
.7 (2
29/2
144)
Chro
nic
kidn
ey
dysf
uncti
on3.
2 (2
60/8
241)
3.2
(243
/750
7)2.
2 (1
6/71
6)3.
5 (2
31/6
636)
1.8
(29/
1605
)2.
0 (1
23/6
097)
6.4
(137
/214
4)
COPD
6.1
(502
/824
1)6.
0 (4
50/7
507)
7.3
(52/
716)
6.2
(413
/663
6)5.
5 (8
9/16
05)
4.8
(292
/609
7)9.
8 (2
10/2
144)
Hear
t fai
lure
5.8
(482
/824
1)5.
8 (4
33/7
507)
6.6
(47/
716)
6.1
(404
/663
6)4.
9 (7
8/16
05)
4.7
(289
/609
7)9.
0 (1
93/2
144)
Obs
truc
tive
sleep
ap
noea
2.2
(181
/824
1)1.
2 (9
2/75
07)
12.4
(89/
716)
2.0
(135
/663
6)2.
9 (4
6/16
05)
2.0
(123
/609
7)2.
7 (5
8/21
44)
Neur
omus
cula
r di
seas
e**
1.0
(80/
8241
)1.
0 (7
3/75
07)
1.0
(7/7
16)
1.1
(72/
6636
)0.
5 (8
/160
5)1.
0 (6
1/60
97)
0.9
(19/
2144
)
Live
r dys
func
tion
1.0
(79/
8241
)1.
0 (7
4/75
07)
0.7
(5/7
16)
1.1
(70/
6636
)0.
6 (9
/160
5)0.
7 (4
4/60
97)
1.6
(35/
2144
)
Surg
ical
pro
cedu
re -
a pa
tient
can
have
mor
e th
an o
ne ty
pe o
f sur
gica
l pro
cedu
re
Low
er g
astr
o-in
testi
nal
10.5
(868
/824
1)10
.9 (8
15/7
507)
6.8
(49/
716)
9.4
(621
/663
6)15
.4 (2
47/1
605)
6.3
(386
/609
7)22
.5 (4
82/2
144)
Uppe
r GI,
hepa
to-b
iliar
y, pa
ncre
as
13.8
(113
8/82
41)
12.8
(959
/750
7)24
.7 (1
77/7
16)
6.5
(431
/663
6)44
.0 (7
06/1
605)
10.6
(649
/609
7)22
.8 (4
89/2
144)
Vasc
ular
surg
ery§
3.1
(257
/824
1)3.
2 (2
40/7
507)
2.4
(17/
716)
3.9
(257
/663
6)0.
0 (0
/160
5)2.
9 (1
75/6
097)
3.8
(82/
2144
)
Aorti
c su
rger
y0.
7 (5
9/82
41)
0.7
(54/
7507
)0.
7 (5
/716
)0.
9 (5
9/66
36)
0.0
(0/1
605)
0.3
(17/
6097
)2.
0 (4
2/21
44)
Neur
osur
gery
, hea
d &
ne
ck20
.2 (1
666/
8241
)20
.7 (1
553/
7507
)15
.4 (1
10/7
16)
25.0
(166
1/66
36)
0.3
(5/1
605)
23.9
(145
5/60
97)
9.8
(211
/214
4)
Urol
ogic
al a
nd k
idne
y8.
9 (7
32/8
241)
9.1
(680
/750
7)7.
1 (5
1/71
6)9.
0 (5
99/6
636)
8.3
(133
/160
5)6.
9 (4
22/6
097)
14.5
(310
/214
4)
Gyna
ecol
ogic
al
11.7
(963
/824
1)11
.6 (8
69/7
507)
12.7
(91/
716)
8.1
(537
/663
6)26
.5 (4
26/1
605)
10.9
(665
/609
7)13
.9 (2
98/2
144)
Endo
crin
e su
rger
y2.
0 (1
64/8
241)
2.0
(147
/750
7)2.
4 (1
7/71
6)2.
3 (1
53/6
636)
0.7
(11/
1605
)2.
3 (1
41/6
097)
1.1
(23/
2144
)
Tran
spla
nt0.
4 (3
2/82
41)
0.4
(32/
7507
)0.
0 (0
//71
6)0.
5 (3
0/66
36)
0.1
(2/1
605)
0.1
(5/6
097)
1.3
(27/
2144
)
Plas
tic, c
utan
eous
, bre
ast
10.8
(891
/824
1)10
.9 (8
20/7
507)
9.9
(71/
716)
13.3
(880
/663
6)0.
7 (1
1/16
05)
13.3
(810
/609
7)3.
8 (8
1/21
44)
Bone
, joi
nt, t
raum
a,
spin
e16
.2 (1
337/
8241
)16
.3 (1
220/
7507
)15
.6 (1
12/7
16)
19.8
(131
6/66
36)
1.3
(21/
1605
)18
.7 (1
141/
6097
)9.
1 (1
96/2
144)
Oth
er p
roce
dure
6.1
(500
/824
1)6.
2 (4
64/7
507)
5.0
(36/
716)
6.7
(442
/663
6)3.
6 (5
8/16
05)
7.2
(436
/609
7)3.
0 (6
4/21
44)
Surg
ical
tech
niqu
e - a
pati
ent c
an h
ave
mor
e th
an o
ne ty
pe o
f sur
gica
l pro
cedu
re
Ope
n ab
dom
inal
surg
ery
17.4
(143
4/82
41)
17.5
(131
0/75
07)
16.9
(121
/716
)21
.4 (1
420/
6636
)---
7.0
(424
/609
7)47
.1 (1
010/
2144
)
Lapa
rosc
opic
surg
ery
17.9
(147
8/82
41)
17.0
(127
7/75
07)
27.4
(196
/716
)---
93.0
(149
3/16
05)
15.6
(953
/609
7)24
.5 (5
25/2
144)
Lapa
rosc
opic
ass
isted
su
rger
y1.
8 (1
45/8
241)
1.7
(127
/750
7)2.
5 (1
8/71
6)---
9.0
(144
/160
5)1.
0 (6
2/60
97)
3.9
(83/
2144
)
Perip
hera
l sur
gery
18.7
(154
0/82
41)
18.6
(140
0/75
07)
18.7
(134
/716
)23
.2 (1
538/
6636
)0.
1 (2
/160
5)22
.2 (1
351/
6097
)8.
8 (1
89/2
144)
Oth
er44
.9 (3
702/
8241
)45
.9 (3
447/
7507
)35
.1 (2
51/7
16)
55.7
(369
8/66
36)
0.2
(4/1
605)
54.5
(332
0/60
97)
17.8
(382
/214
4)
Urg
ency
of s
urge
ry#
Ele
ctive
90.8
(748
6/82
40)
90.7
(680
9/75
06)
93.2
(667
/716
)91
.1 (6
047/
6635
)89
.7 (1
439/
1605
)92
.3 (5
629/
6096
)86
.6 (1
857/
2144
)
Urg
ent
7.2
(595
/824
0)7.
3 (5
45/7
506)
5.9
(42/
716)
7.0
(466
/663
5)8.
0 (1
29/1
605)
6.4
(393
/609
6)9.
4 (2
02/2
144)
Em
erge
ncy
1.9
(159
/824
0)2.
0 (1
52/7
506)
1.0
(7/7
16)
1.8
(122
/663
5)2.
3 (3
7/16
05)
1.2
(74/
6096
)4.
0 (8
5/21
44)
LAS VEGAS study
Chap
ter
5
93
Varia
ble
All p
atien
tsBM
I < 3
5 BM
I ≥ 3
5N
on la
paro
scop
icLa
paro
scop
icAR
ISCA
T <
26AR
ISCA
T ≥
26
Chro
nic
co-m
orbi
dity
- a
patie
nt ca
n ha
ve m
ore
than
one
co-m
orbi
dity
Met
asta
tic ca
ncer
4.1
(340
/824
1)4.
3 (3
24/7
507)
2.2
(16/
716)
4.4
(294
/663
6)2.
9 (4
6/16
05)
1.8
(111
/609
7)10
.7 (2
29/2
144)
Chro
nic
kidn
ey
dysf
uncti
on3.
2 (2
60/8
241)
3.2
(243
/750
7)2.
2 (1
6/71
6)3.
5 (2
31/6
636)
1.8
(29/
1605
)2.
0 (1
23/6
097)
6.4
(137
/214
4)
COPD
6.1
(502
/824
1)6.
0 (4
50/7
507)
7.3
(52/
716)
6.2
(413
/663
6)5.
5 (8
9/16
05)
4.8
(292
/609
7)9.
8 (2
10/2
144)
Hear
t fai
lure
5.8
(482
/824
1)5.
8 (4
33/7
507)
6.6
(47/
716)
6.1
(404
/663
6)4.
9 (7
8/16
05)
4.7
(289
/609
7)9.
0 (1
93/2
144)
Obs
truc
tive
sleep
ap
noea
2.2
(181
/824
1)1.
2 (9
2/75
07)
12.4
(89/
716)
2.0
(135
/663
6)2.
9 (4
6/16
05)
2.0
(123
/609
7)2.
7 (5
8/21
44)
Neur
omus
cula
r di
seas
e**
1.0
(80/
8241
)1.
0 (7
3/75
07)
1.0
(7/7
16)
1.1
(72/
6636
)0.
5 (8
/160
5)1.
0 (6
1/60
97)
0.9
(19/
2144
)
Live
r dys
func
tion
1.0
(79/
8241
)1.
0 (7
4/75
07)
0.7
(5/7
16)
1.1
(70/
6636
)0.
6 (9
/160
5)0.
7 (4
4/60
97)
1.6
(35/
2144
)
Surg
ical
pro
cedu
re -
a pa
tient
can
have
mor
e th
an o
ne ty
pe o
f sur
gica
l pro
cedu
re
Low
er g
astr
o-in
testi
nal
10.5
(868
/824
1)10
.9 (8
15/7
507)
6.8
(49/
716)
9.4
(621
/663
6)15
.4 (2
47/1
605)
6.3
(386
/609
7)22
.5 (4
82/2
144)
Uppe
r GI,
hepa
to-b
iliar
y, pa
ncre
as
13.8
(113
8/82
41)
12.8
(959
/750
7)24
.7 (1
77/7
16)
6.5
(431
/663
6)44
.0 (7
06/1
605)
10.6
(649
/609
7)22
.8 (4
89/2
144)
Vasc
ular
surg
ery§
3.1
(257
/824
1)3.
2 (2
40/7
507)
2.4
(17/
716)
3.9
(257
/663
6)0.
0 (0
/160
5)2.
9 (1
75/6
097)
3.8
(82/
2144
)
Aorti
c su
rger
y0.
7 (5
9/82
41)
0.7
(54/
7507
)0.
7 (5
/716
)0.
9 (5
9/66
36)
0.0
(0/1
605)
0.3
(17/
6097
)2.
0 (4
2/21
44)
Neur
osur
gery
, hea
d &
ne
ck20
.2 (1
666/
8241
)20
.7 (1
553/
7507
)15
.4 (1
10/7
16)
25.0
(166
1/66
36)
0.3
(5/1
605)
23.9
(145
5/60
97)
9.8
(211
/214
4)
Urol
ogic
al a
nd k
idne
y8.
9 (7
32/8
241)
9.1
(680
/750
7)7.
1 (5
1/71
6)9.
0 (5
99/6
636)
8.3
(133
/160
5)6.
9 (4
22/6
097)
14.5
(310
/214
4)
Gyna
ecol
ogic
al
11.7
(963
/824
1)11
.6 (8
69/7
507)
12.7
(91/
716)
8.1
(537
/663
6)26
.5 (4
26/1
605)
10.9
(665
/609
7)13
.9 (2
98/2
144)
Endo
crin
e su
rger
y2.
0 (1
64/8
241)
2.0
(147
/750
7)2.
4 (1
7/71
6)2.
3 (1
53/6
636)
0.7
(11/
1605
)2.
3 (1
41/6
097)
1.1
(23/
2144
)
Tran
spla
nt0.
4 (3
2/82
41)
0.4
(32/
7507
)0.
0 (0
//71
6)0.
5 (3
0/66
36)
0.1
(2/1
605)
0.1
(5/6
097)
1.3
(27/
2144
)
Plas
tic, c
utan
eous
, bre
ast
10.8
(891
/824
1)10
.9 (8
20/7
507)
9.9
(71/
716)
13.3
(880
/663
6)0.
7 (1
1/16
05)
13.3
(810
/609
7)3.
8 (8
1/21
44)
Bone
, joi
nt, t
raum
a,
spin
e16
.2 (1
337/
8241
)16
.3 (1
220/
7507
)15
.6 (1
12/7
16)
19.8
(131
6/66
36)
1.3
(21/
1605
)18
.7 (1
141/
6097
)9.
1 (1
96/2
144)
Oth
er p
roce
dure
6.1
(500
/824
1)6.
2 (4
64/7
507)
5.0
(36/
716)
6.7
(442
/663
6)3.
6 (5
8/16
05)
7.2
(436
/609
7)3.
0 (6
4/21
44)
Surg
ical
tech
niqu
e - a
pati
ent c
an h
ave
mor
e th
an o
ne ty
pe o
f sur
gica
l pro
cedu
re
Ope
n ab
dom
inal
surg
ery
17.4
(143
4/82
41)
17.5
(131
0/75
07)
16.9
(121
/716
)21
.4 (1
420/
6636
)---
7.0
(424
/609
7)47
.1 (1
010/
2144
)
Lapa
rosc
opic
surg
ery
17.9
(147
8/82
41)
17.0
(127
7/75
07)
27.4
(196
/716
)---
93.0
(149
3/16
05)
15.6
(953
/609
7)24
.5 (5
25/2
144)
Lapa
rosc
opic
ass
isted
su
rger
y1.
8 (1
45/8
241)
1.7
(127
/750
7)2.
5 (1
8/71
6)---
9.0
(144
/160
5)1.
0 (6
2/60
97)
3.9
(83/
2144
)
Perip
hera
l sur
gery
18.7
(154
0/82
41)
18.6
(140
0/75
07)
18.7
(134
/716
)23
.2 (1
538/
6636
)0.
1 (2
/160
5)22
.2 (1
351/
6097
)8.
8 (1
89/2
144)
Oth
er44
.9 (3
702/
8241
)45
.9 (3
447/
7507
)35
.1 (2
51/7
16)
55.7
(369
8/66
36)
0.2
(4/1
605)
54.5
(332
0/60
97)
17.8
(382
/214
4)
Urg
ency
of s
urge
ry#
Ele
ctive
90.8
(748
6/82
40)
90.7
(680
9/75
06)
93.2
(667
/716
)91
.1 (6
047/
6635
)89
.7 (1
439/
1605
)92
.3 (5
629/
6096
)86
.6 (1
857/
2144
)
Urg
ent
7.2
(595
/824
0)7.
3 (5
45/7
506)
5.9
(42/
716)
7.0
(466
/663
5)8.
0 (1
29/1
605)
6.4
(393
/609
6)9.
4 (2
02/2
144)
Em
erge
ncy
1.9
(159
/824
0)2.
0 (1
52/7
506)
1.0
(7/7
16)
1.8
(122
/663
5)2.
3 (3
7/16
05)
1.2
(74/
6096
)4.
0 (8
5/21
44)
94
Varia
ble
All p
atien
tsBM
I < 3
5BM
I ≥ 3
5N
on la
paro
scop
icLa
paro
scop
icAR
ISCA
T <
26AR
ISCA
T ≥
26
Plan
ned
dura
tion
of su
rger
y
≤ 2
hou
rs69
.5 (5
724/
8233
)69
.9 (5
242/
7499
)65
.6 (4
70/7
16)
68.3
(452
5/66
28)
74.7
(119
9/16
05)
87.0
(529
6/60
89)
20.0
(428
/214
4)
> 2
– 3
hou
rs19
.2 (1
584/
8233
)18
.8 (1
410/
7499
)23
.6 (1
69/7
16)
20.0
(132
6/66
28)
16.1
(258
/160
5)10
.8 (6
55/6
089)
43.3
(929
/214
4)
> 3
hou
rs11
.2 (9
25/8
233)
11.3
(847
/749
9)10
.8 (7
7/71
6)11
.7 (7
77/6
628)
9.2
(148
/160
5)2.
3 (1
38/6
089)
36.7
(787
/214
4)
Dura
tion
of su
rger
y (m
in)†
73.0
(41.
0 –
125.
0)71
.0 (4
0.0
– 12
5.0)
80.0
(50.
0 –
130.
0)75
.0 (4
0.0
– 12
6.0)
68.0
(45.
0 –
118.
0)60
.0 (3
5.0
– 93
.0)
146.
5 (9
4.0
– 21
0.0)
Dura
tion
of a
naes
thes
ia
(min
)††
104.
0 (6
7.0
– 16
5.5)
101.
0 (6
5.0
– 16
3.0)
113.
0 (7
5.0
– 17
1.0)
105.
0 (6
7.0
– 16
5.0)
96.0
(69.
0 –
155.
0)87
.0 (6
0.0
– 12
5.0)
190.
0 (1
25.0
–
260.
0)
Data
is p
rese
nted
as:
med
ian
(QR)
or p
ropo
rtion
(n/N
); BM
I: Bo
dy M
ass
Inde
x; A
SA: A
mer
ican
Soc
iety
of A
nest
hesi
olog
y; $
ARSI
CAT
scor
e <
26 p
redi
cts
a lo
w ri
sk fo
r pos
tope
rativ
e pu
lmon
ary
com
plic
ation
s (PP
Cs);
ARSI
CAT
scor
e ≥
26 p
redi
cts a
n in
term
edia
te to
hig
h ris
k fo
r PPC
s; S
pO2:
Per
iphe
ral O
xyge
n Sa
tura
tion;
*La
bora
tory
val
ues:
hae
mog
lobi
n w
as c
olle
cted
w
hen
avai
labl
e fr
om c
olle
ction
with
in ro
utine
car
e; C
OPD
: Chr
onic
Obs
truc
tive
Pulm
onar
y Di
seas
e; *
*Neu
rom
uscu
lar d
isea
se a
ffecti
ng th
e re
spira
tory
sys
tem
; §Va
scul
ar s
urge
ry is
ca
rotid
end
arte
rect
omy,
aor
tic su
rger
y an
d pe
riphe
ral v
ascu
lar t
aken
toge
ther
; #U
rgen
cy o
f sur
gery
: ele
ctive
: sur
gery
that
is sc
hedu
led
in a
dvan
ce b
ecau
se it
doe
s not
invo
lve
a m
edic
al
emer
genc
y, u
rgen
t: su
rger
y re
quire
d w
ithin
< 4
8 ho
urs,
em
erge
ncy:
non
-ele
ctive
surg
ery
perf
orm
ed w
hen
the
patie
nt’s
life
or w
ell-b
eing
is in
dire
ct je
opar
dy; †
Dura
tion
of su
rger
y is
the
time
betw
een
skin
inci
sion
and
clos
ure
of th
e in
cisio
n. †
†Dur
ation
of a
naes
thes
ia is
the
time
betw
een
star
t ind
uctio
n an
d ex
tuba
tion
or d
ischa
rge
from
ope
ratio
n ro
om if
mec
hani
cal
venti
latio
n re
mai
ned
LAS VEGAS study
Chap
ter
5
95
Discussion
The main findings of the LAS VEGAS study were that: 1) median tidal volume (VT) was 500.0 (454.2 – 550.5) mL or 8.1 (7.2 – 9.1) mL/kg PBW, PEEP level was 4.0 (0.0 – 5.0) cm H2O and recruitment manoeuvres were rarely performed; 2) PPCs occurred frequently within 3 days after surgery and were associated with longer length of hospital stay and mortality; 3) increasing levels of PEEP but not VT size was independently associated with PPCs.
LAS VEGAS is the largest investigation of the association between intraoperative ventilation strategies and PPCs conducted to date. We investigated both preoperative patient–related and procedure–related risk factors combined with intraoperative complications that were identified in previous investigations.1,16–19,23 The prospective design of the study not only improved the completeness of the data collection, but also avoided any effect of time. The international character makes it representative for many countries.
The most frequently chosen VT and respiratory rate represent the default settings on many anaesthesia ventilators, suggesting a lack of individualization. However, VT size was lower than in previous publications on intraoperative ventilation,24–26 implying that VT size has decreased, at least in the countries that participated in this investigation. Our findings further suggest that there is uncertainty on what PEEP level to use during surgery (0 or 5 cm H2O), but that PEEP levels higher than 5 cm H2O are almost never used, even not in patients with a high BMI, or with high risk for PPCs.27,28
In our cohort, PPCs occurred at a higher rate than previously reported.1,19 The most frequent pulmonary complication was need for oxygen excluding supplementation given as standard of care or continuation of preoperative therapy. When this PPC is not considered, the incidence of PPCs was 1.9%. Patients who developed PPCs had a longer stay in hospital and higher mortality. The most frequent intraoperative complication in all groups was hypotension and need for vasoactive drugs, followed by desaturation, mainly in patients with a BMI ≥ 35 kg/m2 and an ARISCAT score ≥ 26. This observation might reflect attempts to reverse alveolar collapse and atelectasis and their hemodynamic side effects.
The results of the multivariable model seem to be in contrast with results from previous investigations. While several randomized controlled trials showed that the use of low VT is associated with improved outcome of intensive care unit patients,3 and a recent metaanalysis suggested that VT is the major factor responsible for lung protection during intraoperative ventilation,11 the present analysis shows that the occurrence of PPCs is not associated with VT size. Also, differently from the results of three recently published randomized controlled trials,8-10 we found that use of level of PEEP ≥ 7 cmH2O is associated with an increased incidence of PPCs. Both in obese and in high risk patients, increasing PEEP was also independently associated with development of PPCs. There are two possible explanations for these discrepancies. First, in patients included in the present cohort, VT size was remarkably lower than in previous investigations in the intensive care unit,6,7 and in the operation room.3,11,30 Indeed, variations in VT were much smaller, and VT was seldom > 10 ml/kg PBW. Consequently, an association between VT size and occurrence of PPCs would likely need a much larger group of patients.
Data is presented as median (QR) or proportion % (n/N); *Chi-square for categorical variables and Mann-Whitney for continuous variables; $Other (e.g. high frequency oscillatory ventilation, jet ventilation, synchronized intermittent mandatory ventilation (SIMV); PBW: predicted body weight, calculated as: 50 + 0.91 x (centimetres of height – 152.4) for males and 45.5 + 0.91 x (centimetres of height – 152.4) for females; ABW: actual body weight; PEEP: positive end-expiratory pressure; Cdyn.calc.: calculated dynamic respiratory compliance: Cdyn = tidal volume / (peak pressure minus PEEP); Cq.stat.: static respiratory compliance; FiO2: fraction inspired oxygen; SpO2: peripheral oxygen saturation; etCO2: expiratory carbon dioxide
Data is presented as median (QR) or proportion % (n/N); *Chi-square for categorical variables and Mann-Whitney for continuous variables; $Other (e.g. high frequency oscillatory ventilation, jet ventilation, synchronized intermittent mandatory ventilation (SIMV); PBW: predicted body weight, calculated as: 50 + 0.91 x (centimetres of height – 152.4) for males and 45.5 + 0.91 x (centimetres of height – 152.4) for females; ABW: actual body weight; PEEP: positive end-expiratory pressure; Cdyn.calc.: calculated dynamic respiratory compliance: Cdyn = tidal volume / (peak pressure minus PEEP); Cq.stat.: static respiratory compliance; FiO2: fraction inspired oxygen; SpO2: peripheral oxygen saturation; etCO2: expiratory carbon dioxide
98
Table 3. Intraoperative complications
Variable All patients BMI < 35 BMI ≥ 35 p value* Non laparoscopic Laparoscopic p-value* ARISCAT < 26 ARISCAT ≥ 26 p value*
All complications presented as proportion % (n/N); *Chi-square for categorical variables; Definitions intraoperative complications: Any de–saturation: defined as occurrence of SpO2 < 92%; Unplanned recruitment manoeuvre: ventilation strategies aimed to restore lung aeration; ventilation pressure reduction: ventilation strategies aimed to lower peak and/or plateau pressures; Expiratory flow limitation: defined as expiratory flow higher than zero at end-expiration as suggested by visual analysis of the flow curve; Hypotension: defined as SAP < 90mmHg for 3 min or longer; Need for vaso-active drugs: any vaso-active drug given to correct hypotension; New onset arrhythmias: defined as new onset of atrial fibrillation, sustained ventricular tachycardia, supraventricular tachycardia, and ventricular fibrillation
Table 4. Postoperative outcome measures
Variable All patients BMI < 35 BMI ≥ 35 p value* Non-Laparoscopic Laparoscopic p value* ARISCAT < 26 ARISCAT ≥ 26 p value*
All data is presented as proportion, % (n/N) or median (QR); *Comparison of differences within a subgroup is performed by using the t-test for continuous variables; BMI: body mass index in kg/m2; ARISCAT: Assess Respiratory Risk in Surgical Patients in Catalonia (score); PPCs: Postoperative pulmonary complications; ARDS: the acute respiratory distress syndrome; LOS: length of hospital stay; PPCs: on day 1 to 5 were scored YES as soon as the event occurred on either ward or intensive care unit; #Total PPCs: one patient could present with multiple PPCs, but was scored only once (YES or NO principle); $Need for O2 therapy, when not given as standard of care; **Hospital-free days when discharged and alive at day 28
LAS VEGAS study
Chap
ter
5
99
Table 3. Intraoperative complications
Variable All patients BMI < 35 BMI ≥ 35 p value* Non laparoscopic Laparoscopic p-value* ARISCAT < 26 ARISCAT ≥ 26 p value*
All complications presented as proportion % (n/N); *Chi-square for categorical variables; Definitions intraoperative complications: Any de–saturation: defined as occurrence of SpO2 < 92%; Unplanned recruitment manoeuvre: ventilation strategies aimed to restore lung aeration; ventilation pressure reduction: ventilation strategies aimed to lower peak and/or plateau pressures; Expiratory flow limitation: defined as expiratory flow higher than zero at end-expiration as suggested by visual analysis of the flow curve; Hypotension: defined as SAP < 90mmHg for 3 min or longer; Need for vaso-active drugs: any vaso-active drug given to correct hypotension; New onset arrhythmias: defined as new onset of atrial fibrillation, sustained ventricular tachycardia, supraventricular tachycardia, and ventricular fibrillation
Table 4. Postoperative outcome measures
Variable All patients BMI < 35 BMI ≥ 35 p value* Non-Laparoscopic Laparoscopic p value* ARISCAT < 26 ARISCAT ≥ 26 p value*
All data is presented as proportion, % (n/N) or median (QR); *Comparison of differences within a subgroup is performed by using the t-test for continuous variables; BMI: body mass index in kg/m2; ARISCAT: Assess Respiratory Risk in Surgical Patients in Catalonia (score); PPCs: Postoperative pulmonary complications; ARDS: the acute respiratory distress syndrome; LOS: length of hospital stay; PPCs: on day 1 to 5 were scored YES as soon as the event occurred on either ward or intensive care unit; #Total PPCs: one patient could present with multiple PPCs, but was scored only once (YES or NO principle); $Need for O2 therapy, when not given as standard of care; **Hospital-free days when discharged and alive at day 28
100
Second, in randomized controlled trials in abdominal surgery patients benefit was found from a bundle of interventions, namely higher levels of PEEP, recruitment manoeuvres and lower VT, making it impossible to determine which of these factors contributed to the protection against PPCs. Also, we cannot rule out the possibility that one of the elements of the bundle was not beneficial or even harmful, and that such effect might have been masked by the other elements. The results of our present analysis suggest that during low VT ventilation, a level of PEEP ≥ 7 cmH2O is associated with higher incidence of PPCs.
The association between increasing PEEP levels and the occurrence of PPCs suggest a possible detrimental effect of intraoperative PEEP to non–injured lungs, challenging a recent retrospective study.31 Several trials implied a possible benefit of higher levels of PEEP.8–10 Notably, these trials tested a combination of lower VT plus higher levels of PEEP, precluding any conclusion regarding what intervention effectively reduced PPCs. In fact, a level of PEEP of as high as 12 cm H2O did not protect against occurrence of PPCs in patients undergoing open abdominal surgery.32 Theoretically, too high levels of PEEP could increase the end–inspiratory pressures, and cause overdistention on lung tissue that remains aerated at the end of expiration. Indeed, in the present study increasing levels of peak pressure were associated with a higher incidence of PPCs.
Figure 3. The proportion of patients without development of any postoperative pulmonary complication by postoperative day 6 presented by a Kaplan-Meier graph for all patientsPatients with body mass index (BMI) lower than 35 kg/m2 versus equal or higher than 35 kg/m2 (P < 0.0001, log–rank test); patients undergoing laparoscopic versus non–laparoscopic surgery (P = 0.420, log–rank test); and patients with a low versus high risk for PPCs, according to the ARISCAT score (lower versus equal and higher than 26) (P < 0.0001, log–rank test)
LAS VEGAS study
Chap
ter
5
101Figure 4. PROBIT logistic regression analysisDose-response relationship curve between the level of PEEP (cm H2O) used during general anaesthesia for surgery and the probability of postoperative pulmonary complications. The line represents the cubic term fitting all the points
The observation that patients with a BMI ≥ 35 kg/m2 were ventilated with higher VT might be explained by the fact that patient height is not routinely measured during the preoperative visit, and easily overestimated in obese patients. The slightly higher level of PEEP and FiO2 levels used in patients with BMI ≥ 35 kg/m2, or undergoing laparoscopic surgery, likely reflect measures to prevent or treat atelectasis and hypoxemia. In contrast, the combination of higher levels of PEEP with lower FiO2 in patients with an ARISCAT score ≥ 26 might reflect the concept of protective ventilation in previously injured lungs.
This study knows several limitations. First, the observational character of this study does not make it possible to determine any cause-effect relationship. Second, willingness of participating centres to join the study may have caused a selection bias towards interest in protective ventilation, i.e., using low VT, during general anaesthesia for surgery. Third, any prospective observational study can interfere with daily practice, meaning that anaesthetists could have been more eager to use those ventilation settings that are considered lung–protective. Fourth, we had no restriction in number of centres per country, which could have caused an overrepresentation of countries. Fifth, the majority of the participating centres were teaching hospitals with a median of 600 hospital beds and 15 operating theatres. And last, we were not able to collect data on postoperative incidence of atelectasis.
Conclusions
The most common ventilator setting during non–thoracic surgery includes VT < 10 mL/kg and levels of PEEP of 0 or 5 cm H2O. Recruitment manoeuvres are seldom performed. The incidence of PPCs was as high as 10.4%, and independently associated with increasing PEEP levels, but not VT size.
102
Tabl
e 5.
Mul
tivar
iabl
e Lo
gisti
c Re
gres
sion
Usi
ng G
ener
aliz
ed L
inea
r Mix
ed M
odel
s
Varia
ble
Ove
rall
Coho
rtBM
I ≥ 3
5 kg
/m2
Lapa
rosc
opic
Sur
gery
ARIS
CAT
≥ 26
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Venti
latio
n se
tting
s
Tida
l vol
ume,
mL/
kg P
BW---
0.94
(0.8
1 –
1.08
), 0.
387
1.05
(0.9
1 –
1.22
), 0.
476
---
PEEP
, cm
H 2O
1.06
(1.0
1 –
1.12
), 0.
020
1.13
(1.0
1 –
1.26
), 0.
032
1.10
(0.9
9 –
1.22
), 0.
058
1.07
(1.0
1 –
1.14
), 0.
031
Peak
pre
ssur
e, c
mH 2
O1.
03 (1
.00
– 1.
06),
0.04
01.
09 (1
.03
– 1.
15),
0.00
31.
01 (0
.96
– 1.
07),
0.62
1---
F iO2
1.00
(0.9
9 –
1.01
), 0.
885
---1.
00 (0
.99
– 1.
01),
0.99
6---
Patie
nt c
hara
cter
istic
s
Mal
e se
x0.
99 (0
.79
– 1.
25),
0.96
6---
------
BMI,
kg/m
21.
01 (0
.99
– 1.
03),
0.08
1---
1.03
(0.9
9 –
1.06
), 0.
074
---
COPD
1.34
(0.9
7 –
1.86
), 0.
088
---0.
90 (0
.34
– 2.
38),
0.83
31.
68 (1
.06
– 2.
68),
0.02
8
Age,
yea
rs
≤ 50
51
– 8
0
> 80
1 (R
efer
ence
)1.
96 (1
.50
– 2.
59),
< 0.
0001
3.12
(1.7
9 –
5.42
), <
0.00
01
1 (R
efer
ence
)1.
89 (1
.03
– 3.
47),
0.03
92.
26 (0
.33
– 15
.59)
, 0.4
06
1 (R
efer
ence
)2.
00 (1
.24
– 3.
23),
0.00
41.
37 (0
.49
– 3.
82),
0.54
4
1 (R
efer
ence
)1.
70 (1
.17
– 2.
46),
0.00
52.
81 (1
.61
– 4.
88),
< 0.
0001
Func
tiona
l Sta
tus
In
depe
nden
t
Parti
ally
dep
ende
nt
Tota
lly d
epen
dent
1 (R
efer
ence
)1.
54 (1
.00
– 2.
35),
0.04
71.
93 (0
.95
– 3.
92),
0.06
9
---1
(Ref
eren
ce)
1.65
(0.5
8 –
4.70
), 0.
352
4.51
(0.3
2 –
63.4
8), 0
.264
1 (R
efer
ence
)1.
21 (0
.74
– 1.
98),
0.44
80.
99 (0
.32
– 3.
12),
0.99
7
Curr
ent s
mok
er0.
83 (0
.65
– 1.
05),
0.12
0---
------
Resp
irato
ry in
fecti
on1.
68 (1
.09
– 2.
58),
0.01
91.
84 (0
.77
– 4.
42),
0.17
02.
35 (0
.98
– 5.
62),
0.05
5---
Preo
pera
tive
SpO
2, %
≥
96
91 –
95
≤
90
1 (R
efer
ence
)1.
39 (1
.10
– 1.
76),
0.00
52.
55 (1
.26
– 5.
15),
0.00
9
1 (R
efer
ence
)1.
01 (0
.54
– 1.
89),
0.96
93.
09 (0
.86
– 11
.01)
, 0.0
82
1 (R
efer
ence
)1.
57 (0
.91
– 2.
69),
0.10
13.
81 (0
.47
– 30
.91)
, 0.2
10
1 (R
efer
ence
)1.
13 (0
.81
– 1.
57),
0.47
71.
83 (0
.93
– 3.
59),
0.07
9
Preo
pera
tive
anae
mia
1.92
(1.1
8 –
3.14
), 0.
009
---2.
58 (0
.76
– 8.
74),
0.12
7---
Surg
ical
cha
ract
eris
tics
Non
-lapa
rosc
opic
surg
ery
------
---0.
84 (0
.63
– 1.
14),
0.26
8
Urg
ency
of s
urge
ry
Elec
tive
U
rgen
cy
Emer
genc
y
1 (R
efer
ence
)1.
55 (1
.09
– 2.
21),
0.01
42.
63 (1
.44
– 4.
82),
0.00
2
1 (R
efer
ence
)1.
26 (0
.48
– 3.
33),
0.63
72.
21 (0
.37
– 13
.03)
, 0.3
79---
1 (R
efer
ence
)1.
76 (1
.07
– 2.
91),
0.02
72.
61 (1
.12
– 6.
08),
0.02
6
Plan
ned
dura
tion
of s
urge
ry, h
ours
≤
2
2 –
3
> 3
1 (R
efer
ence
)1.
44 (1
.13
– 1.
83),
0.00
32.
16 (1
.60
– 2.
91),
< 0.
0001
1 (R
efer
ence
)1.
14 (0
.67
– 1.
93),
0.63
01.
31 (0
.55
– 3.
12),
0.53
5
1 (R
efer
ence
)1.
89 (0
.99
– 3.
62),
0.05
41.
98 (0
.91
– 4.
32),
0.08
6
1 (R
efer
ence
)1.
14 (0
.77
– 1.
69),
0.51
91.
31 (0
.78
– 2.
19),
0.30
7
Type
of i
ncis
ion
Pe
riphe
ral
Ab
dom
inal
1 (R
efer
ence
)1.
30 (0
.96
– 1.
75),
0.09
11
(Ref
eren
ce)
1.38
(0.7
9 –
2.41
), 0.
262
------
Intr
aope
rativ
e ch
arac
teris
tics
Flui
d in
take
, mill
ilitr
es
≤ 99
9
1000
– 1
999
20
00 –
299
9
≥ 30
00
1 (R
efer
ence
)1.
58 (1
.13
– 2.
23),
0.00
92.
19 (1
.41
– 3.
42),
0.00
12.
93 (1
.78
– 4.
82),
< 0.
0001
1 (R
efer
ence
)0.
99 (0
.47
– 2.
09),
0.99
21.
79 (0
.68
– 4.
74),
0.23
93.
19 (1
.10
– 9.
29),
0.03
3
1 (R
efer
ence
)1.
28 (0
.63
– 2.
62),
0.49
00.
93 (0
.28
– 3.
04),
0.90
72.
46 (0
.80
– 7.
57),
0.11
8
1 (R
efer
ence
)1.
62 (1
.00
– 2.
61),
0.04
91.
65 (0
.94
– 2.
90),
0.08
02.
21 (1
.24
– 3.
95),
0.00
7
Epid
ural
ana
esth
esia
1.22
(0.8
7 –
1.71
), 0.
253
1.84
(0.5
7 –
6.01
), 0.
309
2.56
(1.3
3 –
4.94
), 0.
005
1.02
(0.7
2 –
1.46
), 0.
894
No
use
of n
euro
mus
cula
r blo
ckin
g ag
ents
0.85
(0.5
8 –
1.23
), 0.
387
0.74
(0.2
2 –
2.54
), 0.
632
0.35
(0.0
3 –
4.00
), 0.
399
---
Desa
tura
tion
2.23
(1.4
1 –
3.54
), <
0.00
013.
34 (1
.59
– 7.
02),
0.00
12.
17 (0
.76
– 6.
16),
0.14
52.
20 (1
.27
– 3.
79),
0.00
5
LAS VEGAS study
Chap
ter
5
103
Tabl
e 5.
Mul
tivar
iabl
e Lo
gisti
c Re
gres
sion
Usi
ng G
ener
aliz
ed L
inea
r Mix
ed M
odel
s
Varia
ble
Ove
rall
Coho
rtBM
I ≥ 3
5 kg
/m2
Lapa
rosc
opic
Sur
gery
ARIS
CAT
≥ 26
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Venti
latio
n se
tting
s
Tida
l vol
ume,
mL/
kg P
BW---
0.94
(0.8
1 –
1.08
), 0.
387
1.05
(0.9
1 –
1.22
), 0.
476
---
PEEP
, cm
H 2O
1.06
(1.0
1 –
1.12
), 0.
020
1.13
(1.0
1 –
1.26
), 0.
032
1.10
(0.9
9 –
1.22
), 0.
058
1.07
(1.0
1 –
1.14
), 0.
031
Peak
pre
ssur
e, c
mH 2
O1.
03 (1
.00
– 1.
06),
0.04
01.
09 (1
.03
– 1.
15),
0.00
31.
01 (0
.96
– 1.
07),
0.62
1---
F iO2
1.00
(0.9
9 –
1.01
), 0.
885
---1.
00 (0
.99
– 1.
01),
0.99
6---
Patie
nt c
hara
cter
istic
s
Mal
e se
x0.
99 (0
.79
– 1.
25),
0.96
6---
------
BMI,
kg/m
21.
01 (0
.99
– 1.
03),
0.08
1---
1.03
(0.9
9 –
1.06
), 0.
074
---
COPD
1.34
(0.9
7 –
1.86
), 0.
088
---0.
90 (0
.34
– 2.
38),
0.83
31.
68 (1
.06
– 2.
68),
0.02
8
Age,
yea
rs
≤ 50
51
– 8
0
> 80
1 (R
efer
ence
)1.
96 (1
.50
– 2.
59),
< 0.
0001
3.12
(1.7
9 –
5.42
), <
0.00
01
1 (R
efer
ence
)1.
89 (1
.03
– 3.
47),
0.03
92.
26 (0
.33
– 15
.59)
, 0.4
06
1 (R
efer
ence
)2.
00 (1
.24
– 3.
23),
0.00
41.
37 (0
.49
– 3.
82),
0.54
4
1 (R
efer
ence
)1.
70 (1
.17
– 2.
46),
0.00
52.
81 (1
.61
– 4.
88),
< 0.
0001
Func
tiona
l Sta
tus
In
depe
nden
t
Parti
ally
dep
ende
nt
Tota
lly d
epen
dent
1 (R
efer
ence
)1.
54 (1
.00
– 2.
35),
0.04
71.
93 (0
.95
– 3.
92),
0.06
9
---1
(Ref
eren
ce)
1.65
(0.5
8 –
4.70
), 0.
352
4.51
(0.3
2 –
63.4
8), 0
.264
1 (R
efer
ence
)1.
21 (0
.74
– 1.
98),
0.44
80.
99 (0
.32
– 3.
12),
0.99
7
Curr
ent s
mok
er0.
83 (0
.65
– 1.
05),
0.12
0---
------
Resp
irato
ry in
fecti
on1.
68 (1
.09
– 2.
58),
0.01
91.
84 (0
.77
– 4.
42),
0.17
02.
35 (0
.98
– 5.
62),
0.05
5---
Preo
pera
tive
SpO
2, %
≥
96
91 –
95
≤
90
1 (R
efer
ence
)1.
39 (1
.10
– 1.
76),
0.00
52.
55 (1
.26
– 5.
15),
0.00
9
1 (R
efer
ence
)1.
01 (0
.54
– 1.
89),
0.96
93.
09 (0
.86
– 11
.01)
, 0.0
82
1 (R
efer
ence
)1.
57 (0
.91
– 2.
69),
0.10
13.
81 (0
.47
– 30
.91)
, 0.2
10
1 (R
efer
ence
)1.
13 (0
.81
– 1.
57),
0.47
71.
83 (0
.93
– 3.
59),
0.07
9
Preo
pera
tive
anae
mia
1.92
(1.1
8 –
3.14
), 0.
009
---2.
58 (0
.76
– 8.
74),
0.12
7---
Surg
ical
cha
ract
eris
tics
Non
-lapa
rosc
opic
surg
ery
------
---0.
84 (0
.63
– 1.
14),
0.26
8
Urg
ency
of s
urge
ry
Elec
tive
U
rgen
cy
Emer
genc
y
1 (R
efer
ence
)1.
55 (1
.09
– 2.
21),
0.01
42.
63 (1
.44
– 4.
82),
0.00
2
1 (R
efer
ence
)1.
26 (0
.48
– 3.
33),
0.63
72.
21 (0
.37
– 13
.03)
, 0.3
79---
1 (R
efer
ence
)1.
76 (1
.07
– 2.
91),
0.02
72.
61 (1
.12
– 6.
08),
0.02
6
Plan
ned
dura
tion
of s
urge
ry, h
ours
≤
2
2 –
3
> 3
1 (R
efer
ence
)1.
44 (1
.13
– 1.
83),
0.00
32.
16 (1
.60
– 2.
91),
< 0.
0001
1 (R
efer
ence
)1.
14 (0
.67
– 1.
93),
0.63
01.
31 (0
.55
– 3.
12),
0.53
5
1 (R
efer
ence
)1.
89 (0
.99
– 3.
62),
0.05
41.
98 (0
.91
– 4.
32),
0.08
6
1 (R
efer
ence
)1.
14 (0
.77
– 1.
69),
0.51
91.
31 (0
.78
– 2.
19),
0.30
7
Type
of i
ncis
ion
Pe
riphe
ral
Ab
dom
inal
1 (R
efer
ence
)1.
30 (0
.96
– 1.
75),
0.09
11
(Ref
eren
ce)
1.38
(0.7
9 –
2.41
), 0.
262
------
Intr
aope
rativ
e ch
arac
teris
tics
Flui
d in
take
, mill
ilitr
es
≤ 99
9
1000
– 1
999
20
00 –
299
9
≥ 30
00
1 (R
efer
ence
)1.
58 (1
.13
– 2.
23),
0.00
92.
19 (1
.41
– 3.
42),
0.00
12.
93 (1
.78
– 4.
82),
< 0.
0001
1 (R
efer
ence
)0.
99 (0
.47
– 2.
09),
0.99
21.
79 (0
.68
– 4.
74),
0.23
93.
19 (1
.10
– 9.
29),
0.03
3
1 (R
efer
ence
)1.
28 (0
.63
– 2.
62),
0.49
00.
93 (0
.28
– 3.
04),
0.90
72.
46 (0
.80
– 7.
57),
0.11
8
1 (R
efer
ence
)1.
62 (1
.00
– 2.
61),
0.04
91.
65 (0
.94
– 2.
90),
0.08
02.
21 (1
.24
– 3.
95),
0.00
7
Epid
ural
ana
esth
esia
1.22
(0.8
7 –
1.71
), 0.
253
1.84
(0.5
7 –
6.01
), 0.
309
2.56
(1.3
3 –
4.94
), 0.
005
1.02
(0.7
2 –
1.46
), 0.
894
No
use
of n
euro
mus
cula
r blo
ckin
g ag
ents
0.85
(0.5
8 –
1.23
), 0.
387
0.74
(0.2
2 –
2.54
), 0.
632
0.35
(0.0
3 –
4.00
), 0.
399
---
Desa
tura
tion
2.23
(1.4
1 –
3.54
), <
0.00
013.
34 (1
.59
– 7.
02),
0.00
12.
17 (0
.76
– 6.
16),
0.14
52.
20 (1
.27
– 3.
79),
0.00
5
104
Varia
ble
Ove
rall
Coho
rtBM
I ≥ 3
5 kg
/m2
Lapa
rosc
opic
Sur
gery
ARIS
CAT
≥ 26
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Mul
tivar
iabl
e M
odel
OR
(95%
CI),
p v
alue
Arrh
ythm
ias
2.01
(0.7
8 –
5.22
), 0.
149
------
2.87
(1.0
5 –
7.86
), 0.
040
Hypo
tens
ion
1.04
(0.7
3 –
1.47
), 0.
833
1.54
(0.7
4 –
3.24
), 0.
250
0.96
(0.5
3 –
1.71
), 0.
882
1.20
(0.8
4 –
1.73
), 0.
319
Nee
d of
vas
oacti
ve d
rugs
1.08
(0.7
2 –
1.62
), 0.
691
0.62
(0.2
6 –
1.51
), 0.
291
0.84
(0.4
2 –
1.66
), 0.
608
0.97
(0.6
1 –
1.55
), 0.
903
Post
oper
ative
cha
ract
eris
tics
No
reve
rsal
of n
euro
mus
cula
r bl
ocka
de1.
32 (0
.99
– 1.
75),
0.05
4---
1.42
(0.8
5 –
2.38
), 0.
175
1.11
(0.7
7 –
1.62
), 0.
568
Post
oper
ative
resid
ual c
urar
isatio
n3.
39 (1
.57
– 7.
29),
0.00
24.
98 (0
.94
– 26
.46)
, 0.0
593.
30 (1
.20
– 9.
07),
0.02
13.
91 (1
.79
– 8.
55),
0.00
1
Varia
bles
with
a p
val
ue a
bove
0.2
in th
e un
ivar
iate
ana
lysis
wer
e ex
clud
ed fr
om th
e m
ultiv
aria
te a
naly
sis a
nd th
e ce
lls o
f the
se v
aria
bles
in th
is ta
ble
wer
e ke
pt b
lank
. CI,
confi
denc
e in
terv
al; B
MI:
body
mas
s in
dex;
ARS
ICAT
sco
re <
26
pred
icts
a lo
w ri
sk fo
r pos
tope
rativ
e pu
lmon
ary
com
plic
ation
s (P
PCs)
; ARI
SCAT
sco
re ≥
26
pred
icts
an
inte
rmed
iate
to h
igh
risk
for P
PCs;
PBW
, pre
dict
ed b
ody
wei
ght;
PEEP
, pos
itive
end
-exp
irato
ry p
ress
ure;
Pea
k pr
essu
re: p
eak
insp
irato
ry p
ress
ure;
FiO
2, in
spire
d fr
actio
n of
oxy
gen;
CO
PD: c
hron
ic o
bstr
uctiv
e pu
lmon
ary
dise
ase;
SpO
2: pe
riphe
ral o
xyge
n sa
tura
tion;
Hb:
hae
mog
lobi
n
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Table 6. Matched by propensity for PPC*
Variables Odds Ratio (95% CI) p value
Tidal volume, mL/kg PBW 0.96 (0.89 – 1.02) 0.178
PEEP, cmH2O 1.08 (1.04 – 1.13) < 0.0001
FiO2 0.99 (0.99 – 1.00) 0.599
Peak pressure, cmH2O 1.02 (1.00 – 1.04) 0.037
PPC, postoperative pulmonary complications; CI, confidence interval; PBW, predicted body weight; PEEP, positive end-expiratory pressure; FiO2, inspired fraction of oxygen; *Matched 1:3, PPC to No PPC, within propensity score of 0.15 or less. Matched by: age, sex, BMI, ARISCAT, preoperative SpO2, functional status, smoking, COPD, chronic co-morbidity, respiratory infection < 30 days, preoperative anaemia, type of surgery, planned duration of surgery, condition of surgery, type of incision, fluid intake, epidural anaesthesia, use of NMBA, reversal of NMBA and residual curarisation. Details on matching are found in eTable 9
106
References1. Mazo V, Sabate S, Canet J et al. Prospective external validation of a predictive score for postoperative pulmonary
complications. Anesthesiology 2014, 121(2):219-2312. Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P. Metaanalysis: ventilation strategies and outcomes of the
acute respiratory distress syndrome and acute lung injury. Ann Intern Med 2009, 151(8):566-5763. Serpa Neto A, Cardoso SO, Manetta JA et al. Association between use of lung-protective ventilation with lower tidal
volumes and clinical outcomes among patients without acute respiratory distress syndrome: a metaanalysis. JAMA 2012, 308(16):1651-1659
4. Serpa Neto A, Nagtzaam L, Schultz M. Ventilation with lower tidal volumes for critically ill patients without the acute respiratory distress syndrome: a systematic translational review and metaanalysis. Curr Opin Crit Care 2014, 20(1):25-32
5. Checkley W, Brower R, Korpak A, Thompson B. Effects of a clinical trial on mechanical ventilation practices in patients with acute lung injury. Am J Respir Crit Care Med 2008, 177(11):1215-1222
6. Esteban A, Frutos-Vivar F, Muriel A et al. Evolution of mortality over time in patients receiving mechanical ventilation. Am J Respir Crit Care Med 2013, 188(2):220-230
7. Needham DM, Colantuoni E, Mendez-Tellez PA et al. Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study. BMJ 2012, 344:e2124
8. Severgnini P, Selmo G, Lanza C et al. Protective mechanical ventilation during general anesthesia for open abdominal surgery improves postoperative pulmonary function. Anesthesiology 2013, 118(6):1307-1321
9. Futier E, Constantin JM, Paugam-Burtz C et al. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med 2013, 369(5):428-437
10. Ge Y, Yuan L, Jiang X, Wang X, Xu R, Ma W. Effect of lung protection mechanical ventilation on respiratory function in the elderly undergoing spinal fusion. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2013, 38(1):81-85
11. Serpa Neto A, Barbas CS, Beiderlinden M, et al for the PROVE Network investigators. Protective ventilation with lower tidal volumes and high PEEP versus conventional ventilation with high tidal volume and low PEEP in patients under general anesthesia for surgery: A systematic review and individual patient data metaanalysis. Anesthesiology 2015, 123(1):66-78
12. Karalapillai D, Weinberg L, Galtieri J, et al. Current ventilation practice during general anaesthesia: a prospective audit in Melbourne, Australia. BMC Anesthesiol 2014;14:85
13. Wanderer JP, Ehrenfeld JM, Epstein RH, et al. Temporal trends and current practice patterns for intraoperative ventilation at U.S. academic medical centers: a retrospective study. BMC Anesthesiol 2015;15:40
14. Güldner A, Kiss T, Serpa Neto A, Hemmes SN et al, for the PROtective VEntilation Network. Intraoperative Protective Mechanical Ventilation for Prevention of Postoperative Pulmonary Complications - a Comprehensive Review of the Role of Tidal Volume, Positive End-Expiratory Pressure and Lung Recruitment Maneuvers. Anesthesiology 2015; 123(3): 692-713
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16. Arozullah AM, Daley J, Henderson WG, Khuri SF. Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. The National Veterans Administration Surgical Quality Improvement Program. Ann Surg 2000, 232(2):242-253
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21. Hemmes SN, de Abreu MG, Pelosi P, Schultz MJ. ESA Clinical Trials Network 2012: LAS VEGAS - Local Assessment of Ventilatory Management during General Anaesthesia for Surgery and its effects on Postoperative Pulmonary Complications: a prospective, observational, international, multicentre cohort study. European journal of anaesthesiology 2013, 30(5):205-207
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Supplementary Appendix to ‘Intraoperative Ventilation Strategies and Patient Outcomes Following Surgery: an International Observational Study (LAS VEGAS)’ List of PROVE Network InvestigatorsWriting committeeSabrine N.T. Hemmes (Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands); Ary Serpa Neto (Department of Critical Care Medicine; Hospital Israelita Albert Einstein; São Paulo, Brazil); Marcelo Gama de Abreu (University Hospital Dresden, Germany); Paolo Pelosi (IRCCS AOU San Martino IST Hospital, University of Genoa, Genoa, Italy); Marcus J. Schultz (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands)
LAS VEGAS Steering Committee:Sabrine N.T. Hemmes (Academic Medical Center, Amsterdam, the Netherlands); Ary Serpa Neto (Department of Critical Care Medicine; Hospital Israelita Albert Einstein; São Paulo, Brazil); Jan M. Binnekade (Academic Medical Center, Amsterdam, the Netherlands); Jaume Canet (Hospital Universitari Germans Trias I Pujol, Barcelona, Spain); Goran Hedenstierna (University Hospital Uppsula, Uppsala, Sweden); Samir Jaber (Saint Eloi University Hospital, Montpellier, France); Michael Hiesmayr (Medical University Vienna, Vienna, Austria); Markus W. Hollmann (Academic Medical Center, Amsterdam, the Netherlands); Gary H. Mills (Sheffield Teaching Hospitals, Sheffield, U.K.); Marcos F. Vidal Melo (Massachusetts General Hospital, Boston, U.S.A.); Rupert Pearse (Queen Mary University of London, London, U.K.); Christian Putensen (University Hospital Bonn, Bonn, Germany); Werner Schmid (Medical University Vienna, Vienna, Austria); Paolo Severgnini (University of Insubria, Varese, Italy); Hermann Wrigge (University of Leipzig, Germany); Marcelo Gama de Abreu (University Hospital Dresden, Dresden, Germany); Paolo Pelosi (IRCCS AOU San Martino IST Hospital, University of Genoa, Genoa, Italy); Marcus J. Schultz (Academic Medical Center, Amsterdam, the Netherlands)
PROVE Network websitewww.provenet.eu
List of LAS VEGAS Network Collaborators
AustriaLKH Graz, Graz: Wolfgang Kroell, Helfried Metzler, Gerd Struber, Thomas WegscheiderAKH Linz, Linz: Hans GombotzMedical University Vienna: Michael Hiesmayr, Werner Schmid, Bernhard Urbanek
Belgium UCL - Cliniques Universitaires Saint Luc Brussels: David Kahn, Mona Momeni, Audrey Pospiech, Fernande Lois, Patrice Forget, Irina GrosuUniversitary Hospital Brussels (UZ Brussel): Jan Poelaert, Veerle van Mossevelde, Marie-Claire van MalderenHet Ziekenhuis Oost Limburg (ZOL), Genk: Dimitri Dylst, Jeroen van Melkebeek, Maud BeranGhent University Hospital, Gent: Stefan de Hert, Luc De Baerdemaeker, Bjorn Heyse, Jurgen Van Limmen, Piet Wyffels, Tom Jacobs, Nathalie Roels, Ann De BruyneMaria Middelares, Gent: Stijn van de Velde
Bosnia and Herzegovina General Hospital “prim Dr Abdulah Nakas” Sarajevo: Marina Juros-Zovko, Dejana Djonoviċ- Omanoviċ
CroatiaGeneral Hospital Cakovec, Cakovec: Selma PernarGeneral Hospital Karlovac, Karlovac: Josip Zunic, Petar Miskovic, Antonio Zilic University Clinical Hospital Osijek, Osijek: Slavica Kvolik, Dubravka Ivic, Darija Azenic-Venzera, Sonja Skiljic, Hrvoje Vinkovic, Ivana OputricUniversity Hospital Rijeka, Rijeka: Kazimir Juricic, Vedran FrkovicGeneral Hospital Dr J Bencevic, Slavonski Brod: Jasminka Kopic, Ivan Mirkovic
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University Hospital Center Split, Split: Nenad Karanovic, Mladen Carev, Natasa DropulicUniversity Hospital Merkur, Zagreb: Jadranka Pavicic Saric, Gorjana Erceg, Matea Bogdanovic DvorscakUniversity Hospital Sveti Duh, Zagreb: Branka Mazul-Sunko, Anna Marija Pavicic, Tanja GoranovicUniversity Hospital, Medical school, “Sestre milosrdnice” (Sister of Charity), Zagreb: Branka Maldini, Tomislav Radocaj, Zeljka Gavranovic, Inga Mladic-Batinica, Mirna Sehovic
Czech RepublicUniversity Hospital Brno, Brno: Petr Stourac, Hana Harazim, Olga Smekalova, Martina Kosinova, Tomas Kolacek, Kamil Hudacek, Michal Drab University Hospital Hradec Kralove, Hradec Kralove: Jan Brujevic, Katerina Vitkova, Katerina JirmanovaUniversity Hospital Ostrava, Ostrava: Ivana Volfova, Paula Dzurnakova, Katarina LiskovaNemocnice Znojmo, Znojmo: Radovan Dudas, Radek Filipsky
Egypt El Sahel Teaching hospital, Cairo: Samir el KafrawyKasr Al-Ainy Medical School, Cairo University: Hisham Hosny Abdelwahab, Tarek Metwally, Ahmed Abdel-RazekBeni Sueif University Hospital, Giza: Ahmed Mostafa El-Shaarawy, Wael Fathy Hasan, Ahmed Gouda AhmedFayoum University Hospital, Giza: Hany Yassin, Mohamed Magdy, Mahdy AbdelhadySuis medical Insurance Hospital, Suis: Mohamed Mahran
Estonia North Estonia Medical Center, Tallinn: Eiko Herodes, Peeter Kivik, Juri Oganjan, Annika AunTartu University Hospital, Tartu: Alar Sormus, Kaili Sarapuu, Merilin Mall, Juri Karjagin
France University Hospital of Clermont-Ferrand, Clermont-Ferrand: Emmanuel Futier, Antoine Petit, Adeline GerardInstitut Hospitalier Franco-Britannique, Levallois-Perret: Emmanuel Marret, Marc SolierSaint Eloi University Hospital, Montpellier: Samir Jaber, Albert Prades
Germany Fachkrankenhaus Coswig, Coswig: Jens Krassler, Simone MerzkyUniversity Hospital Carl Gustav Carus, Dresden: Marcel Gama de Abreu, Christopher Uhlig,Thomas Kiss, Anette Bundy, Thomas Bluth, Andreas Gueldner, Peter Spieth, Martin Scharffenberg, Denny Tran Thiem, Thea KochDuesseldorf University Hospital, Heinrich-Heine University: Tanja Treschan, Maximilian Schaefer, Bea Bastin, Johann Geib, Martin Weiss, Peter Kienbaum, Benedikt PannenDiakoniekrankenhaus Friederikenstift, Hannover: Andre Gottschalk, Mirja Konrad, Diana Westerheide, Ben SchwertfegerUniversity of Leipzig, Leipzig: Hermann Wrigge, Philipp Simon, Andreas Reske, Christian Nestler
Greece “Alexandra” general hospital of Athens, Athens: Dimitrios Valsamidis, Konstantinos Stroumpoulis General air force hospital, Athens: Georgios Anthopoulos, Antonis Andreaou, Dimitris Karapanos Aretaieion University Hospital, Athens: Kassiani Theodorak, Georgios Gkiokas, Marios-Konstantinos TtasoulisAttikon University Hospital, Athens: Tatiana Sidiropoulou, Foteini Zafeiropoulou, Panagiota Florou, Aggeliki PandaziAhepa University Hospital Thessaloniki, Thessaloniki: Georgia Tsaousig, Christos Nouris, Chryssa Pourzitaki,
Israel The Lady Davis Carmel Medical Center, Haifa: Dmitri Bystritski, Reuven Pizov, Arieh Eden
Italy Ospedale San. Paolo Bari, Bari: Caterina Valeria Pesce, Annamaria Campanile, Antonella MarrellaUniversity of Bari “Aldo Moro”, Bari: Salvatore Grasso, Michele De MicheleInstitute for Cancer Research and treatment, Candiolo, Turin: Francesco Bona, Gianmarco Giacoletto, Elena SardoAzienda Ospedaliera per l’emergenza Cannizzaro, Catania: Luigi Giancarlo Vicari SottosantiOspedale Melegnano, Cernuso, Milano: Maurizio SolcaAzienda Ospedaliera – Universitaria Sant’Anna, Ferrara: Carlo Alberto Volta, Savino Spadaro, Marco Verri, Riccardo
110
Ragazzi, Roberto ZoppellariOspedali Riuniti Di Foggia - University of Foggia, Foggia: Gilda Cinnella, Pasquale Raimondo, Daniela La Bella, Lucia Mirabella, Davide D’antiniIRCCS AOU San Martino IST Hospital, University of Genoa, Genoa: Paolo Pelosi, Alexandre Molin, Iole Brunetti, Angelo Gratarola, Giulia Pellerano, Rosanna Sileo, Stefano Pezzato, Luca MontagnaniIRCCS San Raffaele Scientific Institute, Milano: Laura Pasin, Giovanni Landoni, Alberto Zangrillo, Luigi Beretta, Ambra Licia Di Parma, Valentina Tarzia, Roberto Dossi, Marta Eugenia SassoneIstituto europeo di oncologia – ieo, Milano: Daniele Sances, Stefano Tredici, Gianluca Spano, Gianluca Castellani, Luigi Delunas, Sopio Peradze, Marco VenturinoOspedale Niguarda Ca’Granda Milano, Milano: Ines Arpino, Sara SherOspedale San Paolo - University of Milano, Milano: Concezione Tommasino, Francesca Rapido, Paola MorelliUniversity of Naples “Federico II” Naples: Maria Vargas, Giuseppe ServilloPoliclinico “P. Giaccone”, Palermo: Andrea Cortegiani, Santi Maurizio Raineri, Francesca Montalto, Vincenzo Russotto, Antonino GiarratanoAzienda Ospedaliero-Universitaria, Parma: Marco Baciarello, Michela Generali, Giorgia CeratiSanta Maria degli Angeli, Pordenone: Yigal LeykinOspedale Misericordia e Dolce - Usl4 Prato, Prato: Filippo Bressan, Vittoria Bartolini, Lucia ZamideiUniversity hospital of Sassari, Sassari: Luca Brazzi, Corrado Liperi, Gabriele Sales, Laura PistiddaInsubria University, Varese: Paolo Severgnini, Elisa Brugnoni, Giuseppe Musella, Alessandro Bacuzzi
Republic of Kosovo Distric hospital Gjakova, Gjakove: Dalip MuhardriUniversity Clinical Center of Kosova, Prishtina: Agreta Gecaj-Gashi, Fatos SadaRegional Hospital ”Prim.Dr. Daut Mustafa”, Prizren: Adem Bytyqi
Lithuania Medical University Hospital, Hospital of Lithuanian University of Health Sciences, Kaunas: Aurika Karbonskiene, Ruta Aukstakalniene, Zivile Teberaite, Erika SalciuteVilnius University Hospital - Institute of Oncology, Vilnius: Renatas Tikuisis, Povilas MiliauskasVilnius University Hospital - Santariskiu Clinics, Vilnius: Sipylaite Jurate, Egle Kontrimaviciute, Gabija TomkuteMalta Mater Dei Hospital, Msida: John Xuereb, Maureen Bezzina, Francis Joseph Borg
Netherlands Academic Medical Centre, University of Amsterdam: Sabrine Hemmes, Marcus Schultz, Markus Hollmann, Irene Wiersma, Jan Binnekade, Lieuwe BosVU University Medical Center, Amsterdam: Christa Boer, Anne DuvekotMC Haaglanden, Den Haag: Bas in ‘t Veld, Alice Werger, Paul Dennesen, Charlotte SeverijnsWestfriesgasthuis, Hoorn: Jasper De Jong, Jens Hering, Rienk van Beek
NorwayHaukeland University Hospital, Bergen: Stefan Ivars, Ib JammerFørde Central Hospital /Førde Sentral Sykehus, Førde: Alena BreidablikMartina Hansens Hospital, Gjettum: Katharina Skirstad Hodt, Frode Fjellanger, Manuel Vico AvalosBærum Hospital, Vestre Viken, Rud: Jannicke Mellin-Olsen, Elisabeth AnderssonStavanger University Hospital, Stavanger: Amir Shafi-Kabiri
PanamaHospital Santo Tomás, Panama: Ruby Molina, Stanley Wutai, Erick Morais
PortugalHospital do Espírito Santo - Évora, E.P.E, Évora.: Gloria Tareco, Daniel Ferreira, Joana AmaralCentro Hospitalar de Lisboa Central, E.P.E, Lisboa.: Maria de Lurdes Goncalves Castro, Susana Cadilha, Sofia AppletonCentro Hospitalar de Lisboa Ocidental, E.P.E. Hospital de S. Francisco Xavier, Lisboa: Suzana Parente, Mariana Correia, Diogo MartinsSantarem Hospital, Santarem: Angela Monteirosa, Ana Ricardo, Sara Rodrigues
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RomaniaSpital Orasenesc, Bolintin Vale: Lucian HorhotaClinical Emergency Hospital of Bucharest, Bucharest: Ioana Marina Grintescu, Liliana Mirea, Ioana Cristina GrintescuElias University Emergency Hospital, Bucharest: Dan Corneci, Silvius Negoita, Madalina Dutu, Ioana Popescu GarotescuEmergency Institute of Cardiovascular Diseases Inst. ‘’Prof. C. C. Iliescu’’, Bucharest: Daniela Filipescu, Alexandru Bogdan ProdanFundeni Clinical institute - Anaesthesia and Intensive Care, Bucharest: Gabriela Droc, Ruxandra Fota, Mihai PopescuFundeni Clinical institute - Intensive Care Unit, Bucharest: Dana Tomescu, Ana Maria Petcu, Marian Irinel TudoroiuHospital Profesor D Gerota, Bucharest: Alida Moise, Catalin-Traian GuranConstanta County Emergency Hospital, Constanta: Iorel Gherghina, Dan Costea, Iulia CindeaUniversity Emergency County Hospital Targu Mures, Targu Mures: Sanda-Maria Copotoiu, Ruxandra Copotoiu, Victoria Barsan, Zsolt Tolcser, Magda Riciu, Gheorghe Moldovan Septimiu, Mihaly Veres
Russia Krasnoyarsk State Medical University, Krasnoyarsk: Alexey Gritsan, Tatyana Kapkan, Galina Gritsan, Oleg KorolkovBurdenko Neurosurgery Institute, Moscow: Alexander Kulikov, Andrey LubninMoscow Regional Research Clinical Institute, Moscow: Alexey Ovezov, Pavel Prokoshev, Alexander Lugovoy, Natalia AnipchenkoMunicipal Clinical Hospital 7, Moscow: Andrey Babayants, Irina Komissarova, Karginova ZalinaReanimatology Research Institute n.a. Negovskij RAMS, Moscow: Valery Likhvantsev, Sergei Fedorov
Serbia Clinical Center of Vojvodina, Emergency Center, Novisad: Aleksandra Lazukic, Jasmina Pejakovic, Dunja Mihajlovic
SlovakiaNational Cancer Institute, Bratislava: Zuzana Kusnierikova, Maria ZelinkovaF.D. Roosevelt teaching Hospital, Banská Bystrica: Katarina Bruncakova, Lenka PolakovicovaFaculty Hospital Nové Zámky, Nové Zámky: Villiam Sobona
SloveniaInstitute of Oncology Ljubljana, Ljubljana: Barbka Novak-Supe, Ana Pekle-Golez, Miroljub Jovanov, Branka StrazisarUniversity Medical Centre Ljubljana, Ljubljana: Jasmina Markovic-Bozic, Vesna Novak-Jankovic, Minca Voje, Andriy Grynyuk, Ivan Kostadinov, Alenka Spindler-Vesel
Spain Hospital Sant Pau, Barcelona: Victoria Moral, Mari Carmen Unzueta, Carlos Puigbo, Josep FavaHospital Universitari Germans Trias I Pujol, Barcelona: Jaume Canet, Enrique Moret, Monica Rodriguez Nunez, Mar Sendra, Andrea Brunelli, Frederic RodenasUniversity of Navarra, Pamplona: Pablo Monedero, Francisco Hidalgo Martinez, Maria Jose Yepes Temino, Antonio Martinez Simon, Ana de Abajo LarribaCorporacion Sanitaria Parc Tauli, Sabadell: Alberto Lisi, Gisela Perez, Raquel MartinezConsorcio Hospital General Universitario de Valencia, Valencia: Manuel Granell, Jose Tatay Vivo, Cristina Saiz Ruiz, Jose Antonio de Andres IbanezHospital Clinico Valencia, Valencia: Ernesto Pastor, Marina Soro, Carlos Ferrando, Mario Defez Hospital Universitario Rio Hortega, Valladolid: Cesar Aldecoa Alvares-Santullano, Rocio Perez, Jesus Rico
SwedenCentral Hospital in Kristianstad: Monir Jawad, Yousif Saeed, Lars Gillberg
TurkeyUfuk University Hospital Ankara, Ankara: Zuleyha Kazak Bengisun, Baturay Kansu KazbekAkdeniz University Hospital, Antalya: Nesil Coskunfirat, Neval Boztug, Suat Sanli, Murat Yilmaz, Necmiye HadimiogluIstanbul University, Istanbul medical faculty, Istanbul: Nuzhet Mert Senturk, Emre Camci, Semra Kucukgoncu, Zerrin Sungur, Nukhet SivrikozAcibadem University, Istanbul: Serpil Ustalar Ozgen, Fevzi ToramanMaltepe University, Istanbul: Onur Selvi, Ozgur Senturk, Mine Yildiz
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Dokuz Eylül Universitesi Tip Fakültesi, Izmir: Bahar Kuvaki, Ferim Gunenc, Semih Kucukguclu, Sule OzbilginSifa University Hospital, İzmir: Jale Maral, Seyda CanliSelcuk University faculty of medicine, Konya: Oguzhan Arun, Ali Saltali, Eyup AydoganFatih Sultan Mehmet Eğitim Ve Araştirma Hastanesi, Istanbul: Fatma Nur Akgun, Ceren Sanlikarip, Fatma Mine Karaman
UkraineInstitute Of Surgery And Transplantology, Kiev: Andriy MazurZaporizhzhia State Medical University, Zaporizhzhia: Sergiy Vorotyntsev
United KingdomSWARM Research Collaborative: for full list of SWARM contributors please see www.ukswarm.comNorthern Devon Healthcare NHS Trust, Barnstaple: Guy Rousseau, Colin Barrett, Lucia StancombeGolden Jubilee National Hospital, Clydebank, Scotland: Ben Shelley, Helen ScholesDarlington Memorial Hospital, County Durham and Darlington Foundation NHS Trust, Darlington: James Limb, Amir Rafi, Lisa Wayman, Jill DeaneRoyal Derby Hospital, Derby: David Rogerson, John Williams, Susan Yates, Elaine RogersDorset County Hospital, Dorchester: Mark Pulletz, Sarah Moreton, Stephanie JonesThe Princess Alexandra NHS Hospital Trust, Essex: Suresh Venkatesh, Maudrian Burton, Lucy Brown, Cait GoodallRoyal Devon and Exeter NHS Foundation Trust, Exeter: Matthew Rucklidge, Debbie Fuller, Maria Nadolski, Sandeep KusreHospital James Paget University Hospital NHS Foundation Trust, Great Yarmouth: Michael Lundberg, Lynn Everett, Helen NuttRoyal Surrey County Hospital NHS Foundation Trust, Guildford: Maka Zuleika, Peter Carvalho, Deborah Clements, Ben Creagh-BrownKettering General Hospital NHS Foundation Trust, Kettering: Philip Watt, Parizade RaymodeBarts Health NHS Trust, Royal London Hospital, London: Rupert Pearse, Otto Mohr, Ashok Raj, Thais CrearyNewcastle Upon Tyne Hospitals NHS Trust The Freeman Hospital High Heaton, Newcastle upon Tyne: Ahmed Chishti, Andrea Bell, Charley Higham, Alistair Cain, Sarah Gibb, Stephen MowatDerriford Hospital Plymouth Hospitals NHS Trust, Plymouth: Danielle Franklin, Claire West, Gary Minto, Nicholas Boyd Royal Hallamshire Hospital, Sheffield: Gary Mills, Emily Calton, Rachel Walker, Felicity Mackenzie, Branwen Ellison, Helen RobertsMid Staffordshire NHS, Stafford: Moses Chikungwa, Clare JacksonMusgrove Park Hospital, Taunton: Andrew Donovan, Jayne Foot, Elizabeth HomanSouth Devon Healthcare NHS Foundation Trust /Torbay Hospital, Torquay, Torbay: Jane Montgomery, David Portch, Pauline Mercer, Janet Palme Royal Cornwall Hospital, Truro: Jonathan Paddle, Anna Fouracres, Amanda Datson, Alyson Andrew, Leanne WelchMid Yorkshire Hospitals NHS Trust; Pinderfields Hospital, Wakefield: Alastair Rose, Sandeep Varma, Karen Simeson Sandwell and West Birmingham NHS Trust, West Bromich: Mrutyunjaya Rambhatla, Jaysimha Susarla, Sudhakar Marri, Krishnan Kodaganallur, Ashok Das, Shivarajan Algarsamy, Julie ColleyYork Teaching Hospitals NHS Foundation Trust, York: Simon Davies, Margaret Szewczyk, Thomas Smith
United States University of Colorado School of Medicine/University of Colorado Hospital, Aurora: Ana Fernandez- Bustamante, Elizabeth Luzier, Angela AlmagroMassachusetts General Hospital, Boston: Marcos Vidal Melo, Luiz Fernando, Demet SulemanjiMayo Clinic, Rochester: Juraj Sprung, Toby Weingarten, Daryl Kor, Federica Scavonetto, Yeo Tze
AcknowledgementsWe are indebted to all participating research nurses, nurse anaesthetists, surgeons, other physicians and our patients. Without them LAS VEGAS would never have been successful.We also thank Brigitte Leva, Sandrine Damster, and Benoit Plichon from the Research Team at the European Society of Anaesthesiology for their expertise and professional help in coordinating the trial and cleaning the study data of LAS VEGAS.
FundingA research grant of the European Society of Anaesthesiology supported this trial.
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STROBE Statement checklist
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Randomization ProcedureCentres with >180 eligible patients per week are offered the option to reduce their patient cohort by randomization. These centres are identified according to the number of eligible patients per week, as reported in the LAS VEGAS Site Survey.
Distribution:< 180 procedures per week: no randomization180 – 360 procedures per week: randomization to include 50% of their cohort> 360 procedures per week: randomization to include 25% of their cohortOnly eligible, planned patients are suitable for randomization. All Emergency procedures and all procedures performed outside office hours (evening/ night/weekend) must be included and therefore should not enter the randomization program.
Details on randomization:- Randomization program: ALEA (computerized)- Stratified per centre- 1 inlog provided per centre- Random blocks- Variables collected:*Centre name*Date of surgery*Urgency of procedure*Surgical Procedure (same categories as collected in CRF)*Planned duration of surgery (in hours)
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*Age patient (in years)*ASA score (1 to 5 or not available)- Output: INCLUDE vs EXCLUDE
How does it work in practice?1. Inform ESA ([email protected]) if you want to make use of the randomization program2. Make a list of all eligible patients (e.g. print-out of planned surgical procedures that day)3. Randomize each patient4. You will receive output: INCLUDE or EXCLUDE5. Make a list of included patients6. Excluded patients do not have to be recorded or filed7. ALEA patient number generated after randomization does not have to be recorded the Patient
Identification Number generated by OpenClinica should be used. This PIN (Study Subject ID) is produced and provided when an electronic CRF is created for the patient.
Multiple operations within 5 day follow-up:2 scenarios:1. If a patient is re-operated during hospital stay, the study is not stopped and follow-up continues
to discharge. This patient does not enter randomization again.2. If the patient is discharged from the hospital and is re-operated later (re-admission); follow-
up is finished the day of the first discharge. No randomization.
eFigure 1. Length of hospital admission (PPC versus no PPC) The proportion of patients alive and admitted to the hospital by postoperative day 28 compared between patients with any postoperative pulmonary complication versus patients without any postoperative pulmonary complication by postoperative day 5 as presented by a Kaplan-Meier graph (P < 0.0001, log–rank test)
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eFigure 2. In-hospital survival (PPC versus No PPC)The proportion of patients without in-hospital mortality by postoperative day 28 compared between patients with any postoperative pulmonary complication versus patients without any postoperative pulmonary complication by postoperative day 5 as presented by a Kaplan-Meier graph (P < 0.0001, log-rank test)
eFigure 3. Tidal volumes for BMI (Actual versus Predicted Body Weight)Distribution of tidal volumes in mL/kg for actual body weight versus predicted body weight (PBW) in the different obesity classes according to BMI (kg/m2) presented as box plots (median, QR, and ranges). Underweight: BMI < 18.5 kg/m2; No obesity: BMI 18.5 – 24.9 kg/m2; Overweight: BMI 25.0 - 29.9 kg/m2; Obesity Class 1: BMI 30.0 to 34.9 kg/m2; Obesity Class 2: BMI 35.0 to 39.9 kg/m2; Morbid obesity: BMI ≥ 40 kg/m2
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eFigure 4. Probability of postoperative pulmonary complications according to peak pressurePROBIT logistic regression showing the dose-relationship curve between the peak pressure (cm H2O) used during general anaesthesia for surgery and the probability of postoperative pulmonary complications. The line represents the cubic term fitting all the points
eTable 1. Definitions of intraoperative complications
Any de–saturation
Defined as SpO2 < 92%
Need for unplanned recruitment manoeuvre
Defined as ventilation strategies aimed to restore aeration of the lungs
Need for ventilatory pressure reduction
Defined as ventilation strategies aimed to lower peak and plateau pressure
New onset of expiratory flow limitation
Defined as expiratory flow higher than zero at end-expiration as suggested by visual analysis of the flow curve
Hypotension
Defined as SAP < 90 mmHg for 3 min or longer
Need for vaso-active drugs
Any vaso-active drug given to correct hypotension as defined above
Any new arrhythmias
Defined as atrial fibrillation [AF], sustained ventricular tachycardia [VT], supraventricular tachycardia [SVT], or ventricular fibrillation [VF]*
*Atrial fibrillation is defined by characteristic absolute irregularity of R-R intervals and concurrent loss of identifiable P waves in the ECG recordings; Ventricular tachycardia is characterized by ≥3 consecutive QRS complexes with a wide QRS complex at a rate of >100 beats/min and duration of >30 seconds; Supraventricular tachycardia is identified as a narrow QRS complex (<0.12 seconds) and a rate of >180 beats/min; Ventricular fibrillation is defined as chaotic ventricular electrical discharge with marked variability in QRS cycle length, morphology, and amplitude
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eTable 2. Definition recruitment manoeuvres
Incremental PEEP
Stepwise increase in PEEP at constant tidal volume, mostly in steps of 5 cmH20, until peak/plateau airway pressure of above 30 cmH20 is reached. PEEP is sustained for at least 3 breaths and then returned back to baseline ventilation
Tidal volume recruitment
Stepwise increase in tidal volume until peak/plateau airway pressure of above 30 cmH20 is reached at constant PEEP level. At least 3 breaths with the plateau pressure of above 30cmH20 are performed, before returning back to baseline ventilation
Combined tidal and PEEP recruitment
PEEP and tidal volume are both stepwise increased to reach a peak/plateau pressure above 30 cmH20. At least 3 breaths with the plateau pressure of above 30 cmH20 are performed, before returning back to baseline ventilation
Inspiratory holds
Also called CPAP manoeuvres. During this kind of manoeuvre a positive airway pressure above 30 cmH20 is applied for 10 to 30 seconds and then returned back to baseline ventilation
Sustained inflation with bag
Manual hyperinflation using balloon/bag
eTable 3. Definitions of postoperative pulmonary complications*
Unexpected need for oxygen therapy
Supplemental oxygen administered due to PaO2 < 60 mmHg or SpO2 < 90% in room air. This excludes oxygen supplementation given as standard care (e.g. directly after arrival in the PACU)
Respiratory failure
PaO2 < 60 mmHg or SpO2 < 90% despite oxygen therapy, or need for non-invasive mechanical ventilation (NIV)
Mechanical ventilation
Unplanned new or prolonged invasive or non–invasive mechanical ventilation, after discharge from the operation room
ARDS
Definition according to the Berlin definition of ARDS1
Pneumonia
Presence of a new or progressive radiographic infiltrate plus at least two of three clinical features; fever >38°C or >100.4 °F, leucocytosis or leukopenia (WBC count >12,000 cells/mm³ or <4,000 cells/mm³) and purulent secretions
Pneumothorax
Defined as air in the pleural space with no vascular bed surrounding the visceral pleura on the chest X–ray
*Adapted from Canet et al.2
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eTable 4. Full list of participating centres
Country City Institution # Patients
Austria Graz LKH Graz 51
Austria Linz AKH Linz 40
Austria Vienna Medical University Vienna 34
Belgium Brussels UCL - Cliniques Universitaires Saint Luc Brussels 119
Odds ratio according to one unit increase of variable; PBW, predicted body weight; PEEP, positive end-expiratory pressure; Peak pressure: peak inspiratory pressure; FiO2, inspired fraction of oxygen; BMI: body mass index; COPD: chronic obstructive pulmonary disease; SpO2: peripheral oxygen saturation; Hb: haemoglobin
eTable 8. Univariate and multivariate analyses of overall cohort using categories of PEEP and tidal volume (adjusted by the same co-variates describing for the overall cohort in table 5)
Odds ratio according to one unit increase of variable; PBW, predicted body weight; PEEP, positive end-expiratory pressure; Peak pressure: peak inspiratory pressure; FiO2, inspired fraction of oxygen; BMI: body mass index; COPD: chronic obstructive pulmonary disease; SpO2: peripheral oxygen saturation; Hb: haemoglobin
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eTable 11. Univariate and Multivariate Logistic Regression in Patients Under Laparoscopic Surgery (n = 1605)
Odds ratio according to one unit increase of variable; PBW, predicted body weight; PEEP, positive end-expiratory pressure; Peak pressure: peak inspiratory pressure; FiO2, inspired fraction of oxygen; BMI: body mass index; COPD: chronic obstructive pulmonary disease; SpO2: peripheral oxygen saturation; Hb: haemoglobin
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eTable 12. Univariate and Multivariate Logistic Regression in Patients with ARISCAT ≥ 26 (n = 2144)
Odds ratio according to one unit increase of variable; ARISCAT, The Assess Respiratory Risk in Surgical Patients in Catalonia; PBW, predicted body weight; PEEP, positive end-expiratory pressure; Peak pressure: peak inspiratory pressure; FiO2, inspired fraction of oxygen; BMI: body mass index; COPD: chronic obstructive pulmonary disease; SpO2: peripheral oxygen saturation; Hb: haemoglobin
References1. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin
Definition. JAMA 2012, 307(23): 2526-332. Canet J, Gallart L, Gomar C, et al. Prediction of Postoperative Pulmonary Complications in a Population-based
Protective ventilation with lower tidal volumes and high PEEP versus conventional ventilation with high tidal volume and low PEEP in patients under general anesthesia for surgery: A systematic review and individual patient data metaanalysis
Serpa Neto A, Hemmes SNT, Barbas CS, Beiderlinden M, Biehl M, Binnekade JM, Canet C, Fernandez-Bustamante A, Futier E, Gajic O, Hedenstierna G, Hollmann MW, Jaber S, Kozian A, Licker M, Lin WQ, Maslow AD, Memtsoudis SG, Reis Miranda D, Moine P, Ng T, Paparella D, Putensen C, Ranieri M, Scavonetto F, Schilling T, Schmid W, Selmo G, Severgnini P, Sprung J, Sundar S, Talmor D, Treschan T, Unzueta C, Weingarten TN, Wolthuis EK, Wrigge H, Gama de Abreu M, Pelosi P, Schultz MJ, for the PROVE Network investigators.Anesthesiology 2015, May 15 [ePub ahead of print]
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Abstract
Background. Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can prevent postoperative pulmonary complications (PPC). The aim of this individual patient data metaanalysis is to evaluate the individual associations between VT size and PEEP level, and occurrence of PPC.
Methods. Randomized controlled trials comparing protective ventilation (low VT with or without high levels of PEEP) and conventional ventilation (high VT with low PEEP) in patients undergoing general surgery. The primary outcome was development of PPC. Predefined prognostic factors were tested using multivariate logistic regression.
Results. Fifteen randomized controlled trials were included (2.127 patients). There were 97 cases of PPC in 1.118 patients (8.7%) assigned to protective ventilation and 148 cases in 1.009 patients (14.7%) assigned to conventional ventilation (adjusted relative risk [RR], 0.64; 95% confidence interval [CI], 0.46-0.88; p < 0.01). There were 85 cases of PPC in 957 patients (8.9%) assigned to ventilation with low VT and high PEEP levels and 63 cases in 525 patients (12%) assigned to ventilation with low VT and low PEEP levels (adjusted RR, 0.93; 95% CI, 0.64-1.37; p = 0.72). A dose–response relationship was found between the appearance of PPC and VT size (R2 = 0.39), but not between the appearance of PPC and PEEP level (R2 = 0.08).
Conclusion. This data supports the beneficial effects of ventilation with use of low VT in patients undergoing surgery. Further trials are necessary to define the role of intraoperative higher PEEP to prevent PPC during non-open abdominal surgery.
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Introduction
More than 230 million major surgical procedures are undertaken worldwide each year.1 Postoperative complications after major surgery increase resource use and are an important cause of death.2 Postoperative pulmonary complications (PPC) are suggested to have a strong impact on the morbidity and mortality of patients who need major surgery.2
A systematic review and metaanalysis of investigations in patients receiving ventilation during general anaesthesia for surgery suggests benefit from so–called ‘protective’ ventilator strategies that use low tidal volumes (VT) with or without high positive end–expiratory pressure (PEEP) levels.3 Two randomized controlled trials of intraoperative ventilation, published after this metaanalysis, confirm benefit from the combination of low VT and high PEEP levels.4,5 Another recent trial demonstrates no benefit from high PEEP levels with the use of low VT, but shows use of high PEEP levels to be associated with the appearance of intraoperative hypotension and increased need for vasoactive drugs.6 Contrary, a large retrospective study showed that use of low VT during general anaesthesia for surgery is associated with increased 30–day mortality, and the investigators suggest that this negative effect was due to the use of low PEEP.7
To gain a better understanding of the independent role of VT and PEEP on protective mechanical ventilation during surgery, we performed a systematic review and metaanalysis of individual patient data. We aimed to investigate the individual associations between ventilation settings, including VT size and PEEP level, and the appearance of postoperative pulmonary complications. We hypothesize (a) intraoperative ventilation with low VT to protect against postoperative pulmonary complications, and (b) use of high PEEP to add to the beneficial effects of intraoperative ventilation with low VT.
Materials and methods
The full methodology of this metaanalysis, the predefined protocol and the statistical analysis plan has been published previously and is presented in the Supplementary Appendix.8 Due to the high number of patients from randomized controlled trials, we decided to deviate from the original protocol and chose to exclude observational studies (i.e., we used only individual patient data from the randomized controlled trials).
Search strategyWe identified eligible randomized controlled trials by a blind electronic search by two authors of MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) up to April 2014. The sensitive search strategy combined the following Medical Subject Headings and Keywords ([protective ventilation OR lower tidal volume OR low tidal volume OR positive end-expiratory pressure OR positive end expiratory pressure OR PEEP]). All reviewed articles and cross–referenced studies from retrieved articles were screened for pertinent information.
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Selection of studiesRandomized controlled trials eligible for this review compared protective with conventional ventilation in adult patients undergoing general anaesthesia for surgery. Protective ventilation was defined as ventilation using low tidal volume (defined as a tidal volume ≤ 8 ml/kg predicted body weight [PBW]) with or without high levels of PEEP (defined as PEEP ≥ 5 cmH2O) and with or without recruitment manoeuvres. Conventional ventilation was defined as ventilation using high tidal volume (> 8 ml/kg PBW) with or without low levels of PEEP (< 5 cmH2O) and without recruitment manoeuvres. The definition of protective and conventional ventilation was made based on several reports in the literature and according to the previously published protocol.3,4,6,8
Authors independently assessed trial eligibility based on titles, abstracts, full–text reports, and further information from investigators as needed. Corresponding authors of retrieved trials were asked to fill a datasheet with ventilation parameters obtained hourly during the surgical procedure. Data from each trial were checked against reported results, and queries were resolved with the principal investigator. Some of the outcomes in this report may differ slightly from those in published original study reports because we standardized outcome definitions and data analyses.
To identify potential sources of bias, we examined concealment of treatment allocation, blinding of clinical outcome assessments and data analyses, the proportion of patients lost to follow–up, and early stopping prior to enrolment of the target sample. We used the Grading of Recommendations Assessment, Development and Evaluation system to rate the overall quality of the evidence. In this system, randomized clinical trials provide high-quality evidence unless limited by important risk of bias, imprecision, inconsistency, indirectness, or high risk of publication bias.
Outcomes
The predefined primary outcome was development of postoperative pulmonary complications during follow–up (composite of postoperative lung injury, pulmonary infection or barotrauma, as defined by the authors in the original studies). Predefined secondary outcomes included in–hospital mortality; intensive care unit (ICU) length of stay; and hospital length of stay.
Statistical analysisAll patients were analysed in the study group to which they were randomized in the original study (intention-to-treat principle). We used 2–sided t–tests to compare respiratory variables during follow–up and likelihood ratio tests to compare statistical models.
For the primary analysis of development of postoperative pulmonary complications, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using logistic regression. The initial model included age, sex, body mass index, type of surgery, ASA (American Society of Anesthesiology score), type of ventilation, highest PEEP used during surgery, highest plateau pressure achieved during surgery, highest compliance achieved during surgery, and presence of risk factor for postoperative pulmonary complications [defined as shock, pneumonia, blood transfusion and/or sepsis]). Variables with p < 0.2 in the univariate analysis are included in the
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multivariate regression. The final model was developed by dropping each variable in turn from the model and conducting a likelihood-ratio test to compare the full and the nested models. We used a significance level of 0.05 as the cut-off to exclude a variable from the model.
To compare in–hospital time to development of postoperative pulmonary complications and in–hospital time to death for the groups under protective or conventional ventilation, we fitted Cox regression models with the same co–variables. Time–to–event was defined as time from the day of surgery to the event in days. Cox proportional–hazards regression models were used to examine simultaneous effects of multiple covariates on outcomes, censoring a patient’s data at the time of death, hospital discharge, or after 30 days. In all models, the categorical outcome variables were tested for trend with the conventional ventilation group as reference. Kaplan–Meier curves were constructed and log–rank tests were used to determine the univariate significance of the study variables.
A priori subgroup analyses were used to assess the effect of VT in the following predefined subgroups: 1) ASA score (< 3 vs. ≥ 3); 2) presence of risk factors for postoperative pulmonary complications (yes or no, defined as pneumonia, shock, transfusion, and/or sepsis); 3) type of ventilation (volume or pressure controlled); 4) type of surgery (cardiac, abdominal, thoracic, or orthopaedic); 5) body mass index (< 17, 18 – 25, 26 – 30, 31 – 35, or > 35 kg/m2); 6) age (< 65 or ≥ 65 years); and 7) sex (male or female).
To assess the individual effects of PEEP on outcome, all analyses were reassessed post-hoc in patients ventilated with low VT (≤ 8 ml/kg PBW) and stratified between those using low (< 5 cmH2O) or high PEEP levels (≥ 5 cmH2O).4 Also, Kaplan-Meier curves of patients ventilated with PEEP ≥ 5 cmH2O were constructed to compare ventilation with tidal volume ≤ 7 ml/kg PBW vs. 8 – 10 ml/kg PBW vs. > 10 ml/kg PBW. These cut-offs were chosen based on the cut-offs usually used in the literature for low (6 ml/kg PBW) and high tidal volume (10 – 12 ml/kg PBW) and the level between them.4-7 Also, in a post-hoc analysis, we analysed the relationship between four cut-offs of PEEP (0-2, 3-5, 6-8 and ≥ 9 cm H2O, with 0-2 cm H2O as the reference) and tidal volume (3-5, 6-8, 9-11 and ≥ 12 ml/kg PBW with ≥ 12 ml/kg PBW as the reference) with the primary outcome. Finally, in a post-hoc analysis, we analysed recruitment manoeuvres as a dichotomous variable in the regression model, using non-recruitment as reference, and adjusted by the same set of co-variables described above.
PROBIT regression analysis was used to characterize the dose–response relationship between the intra–operative VT size and PEEP level and the probability of postoperative pulmonary complications, while adjusting for the same set of covariates used in the final Cox model. A quadratic term was used in the final model for PEEP and tidal volume. The quadratic term was chosen because we hypothesize that the relationship between PEEP, VT and PPC is curvilinear and the highest-degree term is the second degree. This was confirmed by the inspection of the residuals.
All analyses were conducted with SPSS v.20 (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.) or R v.2.12.0. For all analyses two-sided p values < .05 were considered significant.
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Results
Search results and collection of individual patient dataThe search identified 21 randomized controlled trials of intraoperative ventilation comparing different VT size and PEEP levels. We were not able to collect data from six trials due to the following reasons: the corresponding author could not provide data of interest or had no longer access to the complete database (n = 3),9-11 or the corresponding author could not be contacted (n = 3).12-14 The total enrolment based on 15 trial trials for which individual patient data could be collected was 2.127 patients (Figure 1 and Table 1).4,6,15-26 In one trial the difference between the two groups was restricted to use of recruitment manoeuvres,25 in one trial use of recruitment manoeuvres and PEEP level,6 and in three trials the VT size.18,22,23 In the other trials, both VT size and PEEP level differed between the two arms of the trial. The methodological quality of included trials was high, with 13 trials using concealed randomization, six trials using blind data analysis, and only three trials having minimal lost to follow–up.
Patient characteristics and ventilator settingsPatient characteristics and ventilator settings are shown in Table 2 and Table 3. Patients receiving protective ventilation were ventilated with higher PEEP levels, respiratory rates, plateau pressure,
Table 1. Characteristics of included trials
ml/kg PBW Trials
Wrigge Zupancich Miranda Schilling Wolthuis Lin Weingarten Sundar Treschan Memtsoudis Unzueta Severgnini Futier Maslow Hemmes
Type of surgery General Cardiac Cardiac Thoracic General Thoracic Abdominal Cardiac Abdominal Spine Thoracic Abdominal Abdominal Thoracic Abdominal
Number of centres 01 01 01 01 01 01 01 01 01 01 01 01 07 01 30
Country Germany Italy Dutch Germany Dutch China USA USA Germany USA Spain Italy France USA Europe/USA
Number of patients Protective arm Conventional arm
Stopped early No No No No No No No No No No No No No No No
Tidal volume, ml/kg PBW Protective arm Conventional arm
612 – 15
810 – 12
6 – 86 – 8
510
612
5 – 610
610
610
612
612
6 – 86 – 8
79
6 – 810 – 12
510
88
PEEP, cmH2O Protective arm Conventional arm
100
102 – 3
105
0 – 50 – 5
100
3 – 50
120
Scale 55
80
88
100
6 – 80
50
120 – 2
Jadad score 3 3 4 3 3 2 3 4 4 4 3 4 4 3 4
NS: not specified; PBW: predicted body weight; PEEP: positive end-expiratory pressure; USA: United States of America
and higher PaCO2 levels during intraoperative ventilation, as compared to those receiving conventional ventilation. VT was higher in patients who received conventional ventilation during the whole period of ventilation, as compared to patients receiving protective ventilation.
Associations between intraoperative ventilator settings and the primary and secondary endpointsThe appearance of postoperative pulmonary complications was lower in patients receiving protective ventilation compared to patients receiving conventional ventilation (adjusted relative risk [RR], 0.64; 95% confidence interval [CI], 0.46–0.88; p < 0.01) (Table 4 and Figure 2). In–hospital mortality and length of stay in ICU and hospital were similar between the two groups, though patients who developed a PPC had a higher ICU length of stay (6.3 vs. 1.1 days, p < 0.01), a higher hospital length of stay (20.6 vs. 17.1 days, p = 0.011), and died more frequently (6.8 vs. 1.5%, p < 0.01). There was no significant interaction for the effects of protective ventilation on primary outcome according to predefined subgroup analyses, like the ASA score (p = 0.96 for interaction), type of surgery (p = 0.44 for interaction), body mass index (p = 0.77 for interaction) and sex (p = 0.85 for interaction) (Figure 3).
Associations between PEEP levels and the primary and secondary endpoints in patients ventilated with low VT
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Figure 1. Trial flow
Figure 2. Time to postoperative pulmonary complications, composite endpoint and in-hospital mortality for protective and conventional ventilationCox regression models adjusted for age, ASA, and presence of risk factor for postoperative pulmonary complications. HR: hazard ratio; CI: confidence interval
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Table 5 and 6 presents characteristics and outcome for patients ventilated with low VT and high or low PEEP levels. The appearance of postoperative pulmonary complications was not different for patients receiving high or low PEEP levels in these patients (adjusted RR, 0.93; 95% CI, 0.64–1.37; p = 0.72) (Table 7, Figure 4). In–hospital mortality and length of stay in ICU and hospital were also similar between these two groups. There was no association between higher cut-offs of PEEP and the incidence of PPC compared to 0-2 cmH2O of PEEP (Figure 5). There was no significant interaction for the effects of PEEP on primary outcome according to predefined subgroup analyses (Figure 6). Also, the appearance of postoperative pulmonary complications was not different for patients receiving recruitment manoeuvres (adjusted RR for the whole cohort, 0.72; 95% CI, 0.49–1.05; p = 0.09 and adjusted RR for patients ventilated with tidal volume ≤ 8 ml/kg PBW, 0.84; 95% CI, 0.54–1.29; p = 0.84).
Associations between tidal volume size and the primary and secondary endpoints in patients ventilated with high PEEPIn patients ventilated with PEEP ≥ 5 cmH2O, the appearance of postoperative pulmonary complications was lower only in patients receiving tidal volume ≤ 7 ml/kg PBW compared to patients ventilated with tidal volume > 10 ml/kg PBW (adjusted RR, 0.40; 95% CI, 0.21–0.78;
Figure 3. Relative risk for Study Outcomes According to Subgroups (Protective vs. Conventional Ventilation)The size of the squares is proportional to the number of patients in the subgroup. ASA: American Society of Anesthesiologists; CI: confidence interval
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p < 0.01) (Figure 7). Compared to tidal volume ≥ 12 ml/kg PBW, patients ventilated with tidal volume between 6-8 and 3-5 ml/kg PBW presented a lower incidence of PPC (Figure 8). In–hospital mortality was similar between the groups. There was no significant interaction for the effects of tidal volume on primary outcome according to predefined subgroup analyses (Figure 9).
Dose–response relationship between PEEP level and tidal volume size and postoperative pulmonary complicationsDose–response relationship curves between intraoperative tidal volume size and PEEP levels and appearance of postoperative pulmonary complications are shown in Figure 10A and 10B. A dose–response relationship was found between the appearance of PPC and VT size (R2 for mean quadratic term = 0.39), but not between the appearance of PPC and PEEP level (R2 = 0.08).
Figure 4. Time to postoperative pulmonary complications, composite endpoint and in-hospital mortality for patients ventilated with low tidal volumes and high or low levels of PEEPCox regression models adjusted for age, ASA, and presence of risk factor for postoperative pulmonary complications. HR: hazard ratio; CI: confidence interval; PEEP: positive end-expiratory pressure
Figure 5. Relative risk of postoperative pulmonary complications according to different levels of PEEP and using 0 – 2 cmH2O as reference
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Table 2. Baseline characteristics of included patients
Type of surgery, No. (%) Cardiac Thoracic Abdominal Spine
119 (11)196 (17)793 (71)10 (1)
107 (11)119 (12)769 (76)14 (1)
Risk factor for PPC, No. (%)a
Yes Pneumonia Sepsis Transfusion Shock
143 (13)5 (0.5)5 (0.5)89 (8)44 (4)
149 (15)10 (1)10 (1)89 (9)40 (4)
ASA: American Society of Anesthesiologists; IQR: interquartile range; PPC: postoperative pulmonary complicationsaIndividual patients could have more than one risk factor
Discussion
This individual patient metaanalysis of 2.127 patients ventilated under general anesthesia for surgery from 15 randomized controlled trials shows that intraoperative protective ventilation protects the lung from postoperative pulmonary complications. We found that intraoperative low VT was associated with reduced PPC.
In the intensive care unit, following the publication of ARDSNet low–VT trial in patients with the Acute Respiratory Distress Syndrome (ARDS),27 there has been a progressive decrease in VT size over the last decade from more than 12 ml/kg to less than 9 ml/kg.28-30 These changes were supported by numerous preclinical studies in animals showing that ventilation with high VT was associated with lung inflammation and injury,31 worse oxygenation,32 and vascular dysfunction,33 even in healthy lungs. In the operating room VT size remained unchanged, despite numerous randomized controlled trials suggesting benefit of low VT during intraoperative ventilation.34,35 Lack of knowledge of the existence and under–recognition of postoperative pulmonary complications, as well as the idea that shorter duration of intraoperative ventilation may be less injurious than longer duration of ventilation in the intensive care unit may explain the absence of ventilation
148
practice changes in the operating room.2-4 The present analysis is in accordance with the findings of a previous systematic review and metaanalysis,3 and three randomized controlled trials and showing the benefits of protective ventilation during general anesthesia for surgery.4-6 This metaanalysis helps further in the interpretation and understanding of the individual effects of tidal volume and PEEP.
Experimental studies suggest that high PEEP levels minimize cyclical alveolar collapse and corresponding shear injury to the lungs in patients with ARDS.36,37 Based on this observation, it has been suggested that high PEEP levels could benefit patients with ARDS.38 Randomized controlled trials comparing high PEEP levels with low PEEP levels and one metaanalysis, however, suggest only benefit of high PEEP levels in patients who suffered from severe ARDS.38 Ventilation strategies that use high PEEP levels are associated with potentially dangerous side–effects, including hemodynamic depression and lung overdistention, which could further outweigh the potential benefits.39,40 This was also found in the last randomized controlled trial comparing high with low PEEP levels in patients under intraoperative ventilation with low VT.6 The results of
Figure 6. Relative risk for Study Outcomes According to Subgroups (High vs. Low PEEP)The size of the squares is proportional to the number of patients in the subgroup. ASA: American Society of Anesthesiologists; CI: confidence interval
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Tabl
e 3.
Res
pira
tory
var
iabl
es d
urin
g su
rger
y
Varia
ble
Begi
nnin
g of
Pro
cedu
reM
iddl
e of
Pro
cedu
reEn
d of
Pro
cedu
re
Prot
ectiv
eCo
nven
tiona
lp
valu
ePr
otec
tive
Conv
entio
nal
p va
lue
Prot
ectiv
eCo
nven
tiona
lp
valu
e
Tida
l vol
ume,
ml/k
g PB
W7.
3 ±
1.0
[1,1
14]
10.8
± 1
.5[9
18]
< 0.
017.
8 ±
1.3
[739
]10
.0 ±
1.9
[671
]<
0.01
7.1
± 1.
1[1
,015
]10
.3 ±
1.2
[901
]<
0.01
Plat
eau
pres
sure
, cm
H2O
18.8
± 5
.9[9
50]
15.9
± 4
.8[8
25]
< 0.
0121
.3 ±
6.0
[527
]16
.5 ±
5.1
[466
]<
0.01
18.4
± 5
.4[7
56]
16.8
± 4
.8[6
40]
< 0.
01
PEEP
, cm
H2O
8.6
± 3.
4[1
,011
]1.
3 ±
1.8
[911
]<
0.01
7.3
± 5.
0[7
23]
1.1
± 1.
6[6
20]
< 0.
016.
0 ±
4.6
[1,0
86]
1.1
± 1.
9[9
77]
< 0.
01
Resp
irato
ry ra
te,
mpm
12.4
± 2
.8[9
46]
9.9
± 2.
2[8
36]
< 0.
0113
.0 ±
3.5
[569
]10
.3 ±
2.4
[473
]<
0.01
15.1
± 5
.6[7
96]
10.3
± 2
.8[7
15]
< 0.
01
PaO
2 / F
iO2,
mm
Hg40
4.4
± 14
8.0
[321
]41
5.2
± 16
0.3
[233
]0.
4116
9.1
± 19
4.1
[249
]19
7.9
± 22
3.7
[203
]0.
1433
0.0
± 14
8.5
[371
]30
3.7
± 13
5.9
[281
]0.
02
PaCO
2, m
mHg
42.4
± 6
.0[3
21]
38.5
± 7
.1[2
33]
< 0.
0143
.5 ±
6.8
[249
]38
.7 ±
8.0
[203
]<
0.01
43.7
± 7
.9[3
71]
39.1
± 6
.3[2
81]
< 0.
01
Arte
rial p
H7.
39 ±
0.0
6[3
21]
7.41
± 0
.05
[233
]<
0.01
7.34
± 0
.06
[249
]7.
37 ±
0.0
6[2
03]
< 0.
017.
33 ±
0.0
8[3
71]
7.34
± 0
.10
[281
]0.
17
MPM
: mov
emen
ts p
er m
inut
e; P
BW: p
redi
cted
bod
y w
eigh
t; PE
EP: p
ositi
ve e
nd-e
xpira
tory
pre
ssur
e
150
Table 4. Clinical outcomes in patients undergoing general anesthesia for surgery
Length of ICU stay, days 1 (0 – 2) 1 (0 – 2) –0.20 (–1.41 to 1.00)b 0.73
Length of hospital stay, days 10 (7 – 18) 11 (7 – 18) –0.61 (–2.80 to 1.57)b 0.58
CI: confidence interval; ICU: intensive care unit; RR: relative riska Multivariate regression with the outcome of interest as dependent variable; Ventilation group, age, ASA, and presence of risk factor as independent variablesb Coefficient from a corresponding linear regression model using the same independent variables and random effect as the above-described model
Table 5. Baseline characteristics of included patients ventilated with low tidal volumes
Characteristics High PEEP (n = 957) Low PEEP (n = 525)
Age, years 63.6 ± 12.8 64.2 ± 12.8
Female, No. (%) 350 (37) 200 (38)
Body mass index, kg/m2 25.9 ± 4.4 25.1 ± 4.3
ASA, No. (%) Median (IQR) 1 2 3 4
2.0 (2 – 3)86 (9)488 (51)344 (36)29 (3)
2.0 (2 – 3)63 (12)241 (46)205 (39)16 (3)
Type of surgery, No. (%) Cardiac Thoracic Abdominal Spine
139 (14)70 (8)738 (77)10 (1)
77 (15)53 (10)395 (75)0 (0)
Risk factor for PPC, No. (%)a
Yes Pneumonia Sepsis Transfusion Shock
124 (13)10 (1)5 (0.5) 71 (7)38 (4)
37 (7)10 (2)3 (0.5)19 (4)5 (1)
ASA: American Society of Anesthesiology; PEEP: positive end-expiratory pressure; PPC: postoperative pulmonary complication; aIndividual patients could have more than one risk factor
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151
Tabl
e 6.
Res
pira
tory
var
iabl
es d
urin
g su
rger
y in
pati
ents
ven
tilat
ed w
ith lo
w ti
dal v
olum
es
Varia
ble
Begi
nnin
g of
Pro
cedu
reM
iddl
e of
Pro
cedu
reEn
d of
Pro
cedu
re
Hig
h PE
EPLo
w P
EEP
p va
lue*
Hig
h PE
EPLo
w P
EEP
p va
lue*
Hig
h PE
EPLo
w P
EEP
p va
lue*
Tida
l Vol
ume,
ml/k
g PB
W7.
5 ±
1.0
[827
]7.
8 ±
0.8
[484
]0.
127.
8 ±
0.9
[406
]7.
8 ±
0.9
[376
]0.
956.
7 ±
0.9
[526
]6.
9 ±
1.0
[345
]0.
11
Plat
eau
pres
sure
, cm
H 2O
19.0
± 5
.7[8
16]
16.0
± 4
.5[4
62]
< 0.
0121
.1 ±
6.0
[426
]17
.3 ±
5.5
[358
]<
0.01
18.4
± 5
.5[6
37]
16.7
± 4
.3[3
29]
< 0.
01
PEEP
, cm
H 2O
8.8
± 3.
3[9
04]
1.2
± 1.
2[4
62]
< 0.
017.
7 ±
5.0
[626
]1.
1 ±
1.3
[455
]<
0.01
6.6
± 4.
5[9
45]
1.0
± 1.
4[5
25]
< 0.
01
Resp
irato
ry ra
te, b
pm12
.4 ±
2.8
[811
]11
.4 ±
2.1
[460
]<
0.01
12.9
± 3
.6[4
68]
11.8
± 2
.5[3
59]
< 0.
0115
.6 ±
5.9
[681
]12
.0 ±
2.9
[339
]<
0.01
PaO
2 / F
iO2,
mm
Hg42
2.8
± 14
5.7
[249
]34
2.8
± 14
0.5
[73]
< 0.
0117
4.2
± 22
0.2
[180
]14
8.8
± 10
3.0
[76]
0.33
319.
3 ±
164.
6[2
78]
360.
7 ±
127.
9[1
34]
0.01
PaCO
2, m
mHg
42.2
± 5
.8[2
49]
43.5
± 6
.9[7
3]0.
1044
.0 ±
7.1
[180
]42
.6 ±
6.5
[76]
0.17
43.7
± 8
.3[2
78]
43.0
± 6
.0[1
34]
0.38
Arte
rial p
H7.
39 ±
0.0
6[2
49]
7.39
± 0
.07
[73]
0.79
7.34
± 0
.06
[180
]7.
34 ±
0.0
6[7
6]0.
867.
34 ±
0.0
6[2
78]
7.33
± 0
.10
[134
]0.
19
MPM
: bre
aths
per
min
ute;
PBW
: pre
dict
ed b
ody
wei
ght;
PEEP
: pos
itive
end
-exp
irato
ry p
ress
ure;
*Hi
gher
PEE
P vs
Low
er P
EEP
152
this metaanalysis suggest no benefit from high PEEP levels with use of low VT. Thus, high PEEP should not be standard practice, despite the suggestions of an earlier observational study.7
Recently, a large and well–powered randomized controlled trial in France4 confirmed the beneficial effects of protective ventilation in intermediate-risk and high-risk patients undergoing major surgery. However, protection in this trial could have come from low VT, intermediate levels of PEEP, recruitment manoeuvres or from the combination of the three. Indeed, the use of high tidal volume in the conventional arm could be associated with more harm than beneficial of low tidal volume in protective arm. In an attempt to understand the individual effect of PEEP, an international randomized controlled trial evaluated the effects of high PEEP levels with use of low VT.6 High PEEP levels did not prevent postoperative pulmonary complications, but was associated with more hemodynamic compromise.6
Figure 7. Time to postoperative pulmonary complications, composite endpoint and in-hospital mortality for patients ventilated with PEEP ≥ 5 cmH2O and tidal volume ≤ 7 vs. 8 – 10 vs. > 10 ml/kg PBWCox regression models adjusted for age, ASA, and presence of risk factor for postoperative pulmonary complications. HR: hazard ratio; CI: confidence interval; PBW: predicted body weight
Figure 8. Relative risk of postoperative pulmonary complications according to different tidal volumes and using ≥ 12 ml/kg PBW of tidal volume as referencePBW: predicted body weight
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The absence of an association between a protective ventilation strategy and a lower mortality rate could be expected, since mortality of surgical patients is very low in general, and only 1.2% in the cohort of patients included in the present analysis. However, while we did no found differences in mortality and hospital length of stay in in the different ventilation groups, patients who developed a PPC had a higher ICU length of stay, a higher hospital length of stay, and died more frequently.
In this metaanalysis, variability in treatment over time was overcome by conducting a pooled analysis of data on individual patients. The use of these data allowed us to update the number of patients and follow–up after the original published reports. With individual patient data we have enough power to study different subgroups and also to assess the individual effects of PEEP and tidal volume. Also, to date this study included data on the largest population available for comparison of the benefits of protective ventilation in the surgical setting and postoperative outcome.41
Figure 9. Relative risk for Study Outcomes According to Subgroups (≤ 7 ml/kg PBW vs. > 10 ml/kg PBW) The size of the squares is proportional to the number of patients in the subgroup. ASA: American Society of Anesthesiologists; CI: confidence interval; PBW: predicted body weight
154
This metaanalysis knows limitations. First, not all investigators could provide the data, and, therefore, data from six identified studies were not included.9-14 However, the results of a classical metaanalysis including all but one study14 are in agreement with those found in the present analysis. Thus the assumption can be made that the included studies are reliable representatives of all studies of protective ventilation during surgery.5 Second, since the diagnosis of postoperative lung injury is based on clinical criteria, misclassification of patients might underestimate the observed effect, but this factor should have equally affect the different groups analysed. Third, we do not have information on some important factors that could contribute to the development of postoperative complications, including but not limited to
Figure 10. PROBIT logistic regression showing the dose-relationship curve between the A) mean tidal volume (ml/kg PBW) and B) mean PEEP (cmH2O) used in surgery and the probability of postoperative pulmonary complications Solid line: mean quadratic term; Dashed line: 95% confidence interval. The line represents the quadratic term fitting all the points. The flat line in the PEEP graph suggests that there is neither a positive nor a negative association between a higher level of PEEP and the development of postoperative pulmonary complications. PBW: predicted body weight; PEEP: positive end-expiratory pressure
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fluid balance, use of colloids, recruitment manoeuvres and postoperative analgesia. Fourth, since we collected sufficient data on other PPCs, we deviate from the primary outcome stated in the preliminary protocol (‘development of ARDS’)8 to a stronger outcome (‘development of any PPC’), since PPCs were reported in the majority of retrieved studies. Fifth, different types of surgery were analysed and can be a confounding factor. However, no interaction was found between type of surgery and primary outcome according to the predefined subgroup analyses. Finally, due to the variability between the effects on primary outcome, our analysis on PEEP could be underpowered. In fact the highest PEEP quartile was lower than 1 compared to 0-2 cm H2O PEEP. However, the moderate PEEP group 6-8 cmH2O showed a non-significant increase, and not decrease, in the risk of PPC. Higher PEEP was found not effective to reduce PPC when protective tidal volumes were used during open abdominal surgery.6 Also, most of the studies included in the analysis were not a priori conducted to evaluate PEEP effects. Additional studies are required to test the hypothesis that high levels of PEEP during different type of surgery can protect our patients from postoperative respiratory complications.
In conclusion, this individual patient data metaanalysis shows that intraoperative ventilation with low VT protects against postoperative pulmonary complications. Further trials are necessary to define the role of intraoperative higher PEEP to prevent PPC during non-open abdominal surgery.
Financial supportSupport was provided solely from institutional and/or departmental sources.
Table 7. Clinical outcomes in patients undergoing general anesthesia for surgery ventilated with lower tidal volumes
Length of ICU stay, days 0 (0 – 1) 1 (1 – 2) –0.31 (–1.91 to 1.27)b 0.69
Length of hospital stay, days 10 (7 – 18) 11 (8 – 18) –0.48 (–3.04 to 2.07)b 0.71
CI: confidence interval; ICU: intensive care unit; PEEP: positive end expiratory pressure; RR: relative riskaMultivariate regression with the outcome of interest as dependent variable; Ventilation group, age, ASA, and presence of risk factor as independent variablesbCoefficient from a corresponding linear regression model using the same independent variables and random effect as the above-described model
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31. Hegeman MA, Hemmes SN, Kuipers MT, Bos LD, Jongsma G, Roelofs JJ, van der Sluijs KF, Juffermans NP, Vroom MB, Schultz MJ: The extent of ventilator-induced lung injury in mice partly depends on duration of mechanical ventilation. Crit Care Res Pract 2013; 2013:435236
32. Menendez C, Martinez-Caro L, Moreno L, Nin N, Moral-Sanz J, Morales D, Cogolludo A, Esteban A, Lorente JA, Perez-Vizcaino F: Pulmonary vascular dysfunction induced by high tidal volume mechanical ventilation. Crit Care Med 2013; 41:e149-55
33. Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, Rana R, St Sauver JL, Lymp JF, Afessa B, Hubmayr RD: Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 2004; 32:1817-24
34. Jaber S, Coisel Y, Chanques G, Futier E, Constantin JM, Michelet P, Beaussier M, Lefrant JY, Allaouchiche B, Capdevila X, Marret E: A multicentre observational study of intra-operative ventilatory management during general anaesthesia: Tidal volumes and relation to body weight. Anaesthesia 2012; 67:999-1008
35. Fernández-Perez ER, Sprung J, Afessa B, Warner DO, Vachon CM, Schroeder DR, Brown DR, Hubmayr RD, Gajic O: Intraoperative ventilator settings and acute lung injury after elective surgery: A nested case control study. Thorax 2009; 64:121-7
36. Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM, Quintel M, Russo S, Patroniti N, Cornejo R, Bugedo G: Lung recruitment in patients with the acute respiratory distress syndrome. NEJM 2006; 354:1775-1786
37. Muscedere JG, Mullen JB, Gan K, Slutsky AS: Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994; 149:1327-34
38. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS, Pullenayegum E, Zhou Q, Cook D, Brochard L, Richard JC, Lamontagne F, Bhatnagar N, Stewart TE, Guyatt G: Higher vs Lower Positive End-Expiratory Pressure in Patients With Acute Lung Injury and Acute Respiratory Distress Syndrome - Systematic Review and Metaanalysis. JAMA 2010; 303:865-73
39. Pinsky MR: The hemodynamic consequences of mechanical ventilation: an evolving story. Intensive Care Med 1997; 23:493-503
40. Wakabayashi K, Wilson MR, Tatham KC, O’Dea KP, Takata M: Volutrauma, but not Atelectrauma, Induces Systemic Cytokine Production by Lung-Marginated Monocytes. Crit Care Med 2014; 42:e49-57
41. Melo MF, Eikermann M: Protect the lungs during abdominal surgery: it may change the postoperative outcome. Anesthesiology 2013; 118:1254-7
Chapter 7
Rationale and study design of PROVHILO – a worldwide multicenter randomized controlled trial on protective ventilation during general anesthesia for open abdominal surgery
Background. Postoperative pulmonary complications add to the morbidity and mortality of surgical patients, in particular after general anesthesia > 2 hours for abdominal surgery. Whether a protective mechanical ventilation strategy with higher levels of positive end–expiratory pressure (PEEP) and repeated recruitment manoeuvres; the “open lung strategy”, protects against postoperative pulmonary complications is uncertain. The present study aims at comparing a protective mechanical ventilation strategy with a conventional mechanical ventilation strategy during general anesthesia for abdominal non–laparoscopic surgery.
Methods and design. The PROtective Ventilation using HIgh versus LOw positive end–expiratory pressure (“PROVHILO”) trial is a worldwide investigator-initiated multicenter randomized controlled two-arm study. Nine hundred patients scheduled for non–laparoscopic abdominal surgery at high or intermediate risk for postoperative pulmonary complications are randomized to mechanical ventilation with the level of PEEP at 12 cmH2O with recruitment manoeuvres (the lung–protective strategy) or mechanical ventilation with the level of PEEP at maximum 2 cmH2O without recruitment manoeuvres (the conventional strategy). The primary endpoint is any postoperative pulmonary complication.
Discussion. The PROVHILO trial is the first randomized controlled trial powered to investigate whether an open lung mechanical ventilation strategy in short–term mechanical ventilation prevents against postoperative pulmonary complications.
Trial registration. Current Controlled Trials ISRCTN70332574
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Background
Mechanical ventilation is a life–saving strategy in patients with respiratory failure. There is unequivocal evidence that mechanical ventilation in critically ill patients has the potential to aggravate or even initiate lung injury.1,2 Patients with acute lung injury (ALI) could benefit from measures that prevent repeated collapse and re–expansion of alveoli, including the so–called open lung mechanical ventilation strategy with the use of higher levels of positive end–expiratory pressure (PEEP) and recruitment maneuvers.3 Metaanalysis suggest this approach can waive the need for rescue therapies due to life–threatening hypoxemia,1 and even reduce mortality in patients with more severe ALI.4
Mechanical ventilation is frequently mandatory in patients who undergo surgery. The effects of short term intraoperative mechanical ventilation on pulmonary integrity are less well defined.5 In addition, it is uncertain whether ventilation strategies that use higher levels of PEEP and recruitment manoeuvres during the intraoperative period are beneficial in these patients.6,7 However, higher levels of PEEP could reduce intraoperative atelectasis, decreasing repetitive collapse and re–expansion of dependent lung parts, and thereby attenuating pulmonary inflammation and coagulation.8,9 Use of recruitment manoeuvres to open the lungs has been found to improve the effectiveness of PEEP with regard to gas exchange during general anesthesia.10 Intraoperative use of PEEP does not represent a common practice. Indeed, an observational study conducted in 28 centres in France revealed that most patients undergoing general surgery were ventilated without PEEP.11 Thus, the intraoperative use of PEEP cannot be seen as clinical standard.
Postoperative pulmonary complications, in particular after general anesthesia > 2 hours for abdominal surgery, add to the morbidity and mortality of surgical patients.12,13 We hypothesize that a lung–protective mechanical ventilation strategy with higher levels of PEEP and recruitment manoeuvres attenuates postoperative pulmonary complications in patients without lung injury (i.e., patients who do not fulfil the criteria for ALI at the moment of surgery).
PROVHILO aims at comparing the effects of such protective strategy and conventional mechanical ventilation in biomarkers of lung injury, postoperative pulmonary complications, extra pulmonary complications and length of hospital stay in patients undergoing general anesthesia for open abdominal surgery.
Methods
Objectives and designThe PROtective Ventilation using HIgh versus LOw positive end–expiratory pressure (“PROVHILO”) trial is a worldwide investigator-initiated multicenter randomized controlled two-arm trial.
The Institutional Review Board of the Academic Medical Center – University of Amsterdam, Amsterdam, The Netherlands, approved the trial. The PROVHILO trial is conducted in accordance
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with the declaration of Helsinki and was registered on October 29 2010 at www.controlled-trials.com with trial identification number ISRCTN70332574.
Figure 1. CONSORT diagram of the PROVHILO trial
Study populationLocal investigators screen consecutive patients scheduled for non–laparoscopic abdominal surgery in participating centres worldwide. Demographic data on screened patients regardless of meeting enrolment criteria are recorded (registry: age, gender, type of surgery). A total of 900 patients are randomized to the 2 different mechanical ventilation strategies. In the participating centres at least 2 investigators are involved with the study. One researcher is involved with mechanical ventilation practice in the operation room, he/she will be blinded for the randomized intervention most closely to the time of tracheal intubation (depending on local situation) – the second investigator, blinded for randomization arm, will score the primary and secondary postoperative endpoints.
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Patients with high or intermediate risk for postoperative pulmonary complications following non–laparoscopic abdominal surgery with general anesthesia are eligible for participation. To identify such patients the ARISCAT risk score (see Table 2) will be used.14 This predictive risk index is developed by the ARISCAT Group to assess the individual preoperative risk for post–operative pulmonary complications. An ARISCAT risk score ≥ 26 is associated with an intermediate to high risk for postoperative pulmonary complications.
Patients planned for laparoscopic surgery are excluded from participation, as are non–adult patients (age < 18 years), patients with a body mass index > 40 kg/m2, pregnant patients (excluded by laboratory analysis), and patients who consented for another interventional study or decline to participate. In addition, patients who were on mechanical ventilation > 30 minutes (e.g., because of general anesthesia for surgery) within last 30 days, are excluded. Other important exclusion criteria include: any previous lung surgery, history of previous severe chronic obstructive pulmonary disease (COPD) with (non–invasive) ventilation and/or oxygen therapy at home and/or repeated systemic corticosteroid therapy for acute exacerbations of COPD, ALI or acute respiratory distress syndrome expected to require prolonged post–operative mechanical ventilation, persistent hemodynamic instability or intractable shock (considered hemodynamic unsuitable for the study by the patient’s managing physician), severe cardiac disease (New York Heart Association class III or IV, or acute coronary syndrome, or persistent ventricular tachyarrhythmia’s), and recent immunosuppressive medication (receiving chemotherapy or radiation therapy within last 2 months).
All patients are asked for signed informed consent, as required by the institutional review board in accordance with the Declaration of Helsinki.
Randomization and interventionRandomization is performed using a dedicated, password protected, SSL-encrypted website. Randomization sequence is generated using random blocks and is stratified per centre. No blocking is applied to other trial factors.
Patients are randomly assigned to mechanical ventilation with levels of PEEP at 12 cmH2O with the use of recruitment manoeuvres (the lung–protective strategy) or mechanical ventilation with levels of PEEP at maximum 2 cmH2O without recruitment manoeuvres (the conventional strategy). The PEEP level in the protective strategy is chosen to be 12 cmH2O, to achieve maximal interventional effect without causing harm to participating patients and to make the intervention acceptable for the participating clinicians. The conventional strategy is chosen based on a national survey in France that showed > 90% of responding anaesthetists to use levels of PEEP of 0 – 4 cmH2O without recruitment maneuvers.11 Since not all available anesthesia ventilators can apply levels of PEEP < 2 cmH2O, the level of PEEP is set at a maximum of 2 cmH2O with the conventional strategy. However the lowest possible level of PEEP is always chosen.
Mechanical ventilationPatients are ventilated with a volume–controlled mechanical ventilation strategy. Although it is left to the discretion of the attending anaesthesiologist to use different fractions of inspired oxygen, it is advised to use at least 0.4, with the lowest oxygen fraction to maintain oxygen
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saturation ≥ 92%. The inspiratory to expiratory time ratio (I:E) is set at 1:2, and the respiratory rate is adjusted to reach normocapnia (end–tidal carbon dioxide partial pressure between 35 and 45 mmHg). Tidal volumes of < 8 mL/kg predicted body weight (PBW) are advised to be used [15]. PBW is calculated according to a predefined formula: 50 + 0.91 x (centimetres of height – 152.4) for males and 45.5 + 0.91 x (centimetres of height – 152.4) for females.16,17 Tidal volumes throughout this protocol refer to the actual inspired tidal volume in the ventilator circuit.
Recruitment manoeuvreRecruitment manoeuvres, as part of the lung–protective strategy, are performed directly after intubation, after any disconnection from the mechanical ventilator, and directly before tracheal extubation. Recruitment manoeuvres should not be performed when patients are hemodynamic unstable, as judged by the attending physician.
Recruitment manoeuvres are not easily applied with available anesthesia ventilators since not all machines have an inspiratory hold function or other adequate facilities. To obtain standardization among centres, recruitment manoeuvres are performed as follows:
1. peak inspiratory pressure limit is set at 45 cmH2O
2. tidal volume is set at 8 ml/kg PBW and respiratory rate at 6-8 breaths/min (or lowest respiratory rate that anesthesia ventilator allows), while PEEP is set at 12 cmH2O
3. inspiratory to expiratory ratio (I:E) is set at 1:2
4. tidal volumes are increased in steps of 4 ml/kg PBW until a plateau pressure of 30–35 cmH2O
5. 3 breaths are administered with a plateau pressure of 30 – 35 cmH2O
6. peak inspiratory pressure limit, respiratory rate, I:E, and tidal volume are set back to settings preceding each recruitment manoeuvre, while maintaining PEEP at 12 cmH2O
Protocol drop–outAnesthesiologists are allowed to change the ventilation protocol at any time point upon the surgeon’s request, or if there is any concern about patient’s safety. The level of PEEP can be modified according to the anaesthesiologist in charge if the systolic arterial pressure drops < 90 mmHg for more than 3 minutes despite intravenous fluid infusion and/or start of vasopressors, if dosages of vasopressors are at the highest level tolerated, if new arrhythmias develop which are unresponsive to treatment suggested by the Advanced Cardiac Life Support Guidelines,18 if there is need of massive transfusion to maintain Ht > 21% (Hb > 7 mg/dl), or if there is a surgical complication determining life–threatening situations.
Rescue therapyIn both study groups, in case of desaturation (SpO2 < 90%), after excluding airway problems, severe hemodynamic impairment and ventilator malfunction, a rescue strategy is proposed, which improves oxygenation with respectively a decreasing level of PEEP with increasing FiO2 in
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the lung–protective strategy group, and increasing levels of PEEP and FiO2 in the conventional group (see table 1).
Standard proceduresThe study protocol stresses that routine general anesthesia, postoperative pain management, physiotherapeutic procedures and fluid management must be used in the perioperative as well as the postoperative period according to each centres specific expertise and routine clinical use, to minimize interference with the trial intervention. However, it is suggested to perform postoperative pain management in order to achieve a visual analogue scale (VAS) pain score < 3, to use regional or neuroaxial analgesia if indicated, to use physiotherapy by early mobilization, deep breathing exercises with and without incentive spirometry, and stimulation of cough in the postoperative period, to avoid fluid overload (according to the discretion of the responsible physicians) and to use appropriate prophylactic antibiotics when indicated. Data on the applied procedures will be collected and analysed.
Table 1. Rescue therapies with the protective and the conventional strategy
Follow upBaseline variables are collected pre–operative at the pre–anaesthetic visit or before induction of general anesthesia. The following variables are collected; gender, age, height, weight, functional status (independent, partially dependent or totally dependent), physical status (according to the American Society of Anesthesiologists (ASA), cardiac status (heart failure, according to the New York Heart Association (NYHA), acute coronary syndrome, or persistent ventricular tachyarrhythmia’s), COPD and use of inhalation therapy and/or steroids, respiratory infection in the last month, smoking status, alcohol status in the past 2 weeks, history of active cancer,
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weight loss > 10% in the last 6 months, history of diabetes mellitus, use of oral anti–diabetics, use of antibiotics in the last 3 months, use of statins, type of scheduled surgery (emergency or non–emergency and surgical procedure), transfusion of blood products in the preceding 6 hours, vital parameters (tympanic temperature, respiratory rate, SpO2 (%), blood pressure, heart rate), airway secretion score (the patient is required to cough and the presence of secretion will be subjectively evaluated; if yes: purulent or not), VAS–scores for dyspnoea and pain, blood samples (glycaemia, uraemia, creatinine, AST, ALT, bilirubin, Hb, WBC count, platelet count, PT, PTT, and biomarkers [see below]) and a chest X–ray (assessed on mono- and bilateral infiltrate, pleural effusion, atelectasis, pneumothorax, cardiopulmonary oedema).
During the intraoperative period variables are recorded hourly after induction of anesthesia during the recruitment manoeuvre. These variables include duration and type of both anesthesia and surgical procedures, all administered drugs during anesthesia (e.g. anaesthetics, vasoactive drugs, anti-arrhythmic medication), ventilator settings, vital parameters, fluid– and transfusion requirements, need of rescue therapy for hypoxemia and intraoperative complications possibly related to recruitment manoeuvres (e.g. desaturation, hypotension during recruitment manoeuvre, need for vasoactive medication).
Patients are assessed at the first five postoperative days and at the last day before discharge from the hospital. On day 90 hospital free-days are recorded; if the patient is still admitted to the hospital on day 90, this day will be recorded as last day of follow-up. Clinical data and the presence of pulmonary and extra–pulmonary postoperative complications are scored; the day of development of any complication is indicated. A chest X–ray will be taken on the first post–operative day, blood samples for laboratory tests (glycaemia, uraemia, creatinine, AST, ALT, bilirubin, Hb, WBC count, platelet count, PT, PTT) will be taken on day 1, 3 and 5 and blood samples for biomarkers are collected directly after surgery and on day 5. As mentioned above, one local investigator, blinded for randomization group will score the primary and secondary postoperative endpoints.
Study endpointsPrimary endpoint – is a composed endpoint of all postoperative pulmonary complications with each complication weighing equally; it is presented as a total percentage of post–operative pulmonary complications. The postoperative complications are defined as: (a) mild respiratory failure (PaO2 < 60 mmHg or SpO2 < 90% in room air but responding to supplemental oxygen, (b) severe respiratory failure (need for non–invasive or invasive mechanical ventilation or a PaO2 < 60 mmHg or SpO2 < 90% despite supplemental oxygen), (c) development of ALI/ARDS (according to consensus guidelines),19 (d) suspected pulmonary infection (patient receives antibiotics and meets at least one of the following criteria: new or changed sputum, new or changed lung opacities on chest X–ray when clinically indicated, tympanic temperature > 38.30C, WBC count > 12,000/ml in the absence of other infectious focus), (e) pulmonary infiltrate (chest X–ray demonstrating unilateral or bilateral infiltrates), (f) pleural effusion (chest X–ray demonstrating blunting of the costophrenic angle, loss of the sharp silhouette of the ipsilateral hemidiaphragm in upright position, evidence of displacement of adjacent anatomical structures or (in supine position) a hazy opacity in one hemi–thorax with preserved vascular shadows), (g) atelectasis (suggested by lung opacification with shift of the mediastinum, hilum, or hemidiaphragm towards the affected
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Table 2. ARISCAT risk score Independent predictors of risk for post-operative pulmonary complications identified in the logistic regression model
High or intermediate risk for postoperative pulmonary complications ≥ 26
CI: confidence interval; OR: odds ratio; SpO2: oxyhemoglobin saturation by pulse oximetry breathing air in supine position; g/dL: gram per decilitre †The simplified risk score was the sum of each logistic regression coefficient multiplied by 10, after rounding off its value
area, and compensatory overinflation in the adjacent non-atelectatic lung), (h) pneumothorax (air in the pleural space with no vascular bed surrounding the visceral pleura), (i) bronchospasm (newly detected expiratory wheezing treated with bronchodilators), (j) aspiration pneumonitis (respiratory failure after the inhalation of regurgitated gastric contents), (k) cardiopulmonary
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oedema (clinical signs of congestion, including dyspnoea, oedema, rales and jugular venous distention, with the chest X–ray demonstrating increase in vascular markings and diffuse alveolar interstitial infiltrates).
Secondary clinical endpoints – include (a) intraoperative ventilation strategy related complications (e.g. desaturation, hypotension during recruitment manoeuvre, need for vasoactive medication), (b) unexpected need for ICU admission or ICU readmission, (c) hospital–free days at follow–up day 90, (d) post–operative wound healing and (e) post–operative extra–pulmonary complications. Extra–pulmonary complications include SIRS, sepsis, severe sepsis, septic shock (all according to consensus criteria),20 extra–pulmonary infection (wound infection or any other infection), coma (Glasgow Coma Score < 8 in the absence of therapeutic coma or sedation), acute myocardial infarction (according to universal definition of myocardial infarction),21 acute renal failure (according to the RIFLE classification system),22 disseminated intravascular coagulation (according to ISTH diagnostic scoring system for DIC),23 gastro–intestinal failure (defined as; gastro-intestinal bleeding or gastro-intestinal failure according to GIF–score)24 and hepatic failure (defined as; serum bilirubin level > 2 mg/dL with elevation of the transaminase and lactic dehydrogenase levels above twice normal values).
Other study parameters – Blood samples will be collected and analysed for systemic markers of lung injury (including but not limited to soluble Receptor for Advanced Glycation Endproducts (sRAGE), Clara Cell protein–16 (CC–16), surfactant proteins A and D and levels of proinflammatory and procoagulant/antifibrinolytic mediators (including but not limited to interleukin (IL)–6, IL–8, tumor necrosis factor (TNF)–α, and thrombin–antithrombin (TAT), protein C, and plasminogen activator inhibitor (PAI)–1). The abovementioned biomarkers of lung injury, acute inflammation and coagulopathy have been shown to correlate with poor clinical outcome in patients with ALI/ARDS.25 Notably, with short term mechanical ventilation rises in systemic levels of lung injury biomarkers,26 acute inflammation9 and procoagulant/ antifibrinolytic mediators8 have been described. Lung–protective mechanical ventilation strategies attenuated the rise in levels of some of the abovementioned mediators in patients with ALI/ARDS,27 as well as patients who underwent short term mechanical ventilation because of surgery.8,9 Most of these trials compared the effect of different tidal volumes.
The injury induced by mechanical ventilation originates in the lung, but may also affect distal organs by release of mediators from the lung into the systemic circulation.28,29 Therefore systemic biomarkers of distant organ injury, in particular the kidney, are determined (including, but not limited to neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C).
Statistical considerationsSample size calculation – the required sample size is calculated from an estimated effect size derived from data collected in the ARISCAT study14 and previous studies on the incidence of postoperative pulmonary complications.12,13,30 A two group χ2 test with a 0.05 two–sided significance level will have 80% power to detect the difference (in post–operative pulmonary complications) between conventional mechanical ventilation (24%) and open lung mechanical ventilation (16.5%) (Odds ratio of 0.626) when the sample size in each group is 450.
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Interim analysis – one main concern is not to withhold positive effects of the open lung mechanical ventilation strategy to the control group. Therefore, interim analyses are performed after 300 and 600 patients. The first interim analysis is performed when 300 patients have successfully been included and followed-up. If the intervention has a strong trend for improving postoperative pulmonary complications (as defined above) with a p–value < 0.0005 is found at 300 patients or < 0.014 at 600 patients, termination of the study is considered. The third and final analysis is performed at 900 patients with a p–value of 0.045 for significance. When postoperative pulmonary complications occur significantly more frequent in the intervention group, terminating the study due to harm will be considered when p ≤ 0.022 for each interim analysis.
Statistical analysisNormally distributed variables will be expressed by their mean and standard deviation; not normally distributed variables will be expressed by their medians and interquartile ranges; categorical variables will be expressed as n (%). In test groups of continuous normally distributed variables, Student’s t–test will be used. Likewise if continuous data are not normally distributed the Mann–Whitney U test will be used. Categorical variables will be compared with the Chi–square test or Fisher’s exact tests or when appropriate as relative risks. Where appropriate statistical uncertainty will be expressed by 95% confidence levels.
Primary outcome is the total occurrence of pulmonary complications within the first 5 post–operative days, presented as a percentage. The percentage will be analysed as continuous data. If the data is normally distributed, Student’s t–test will be used or when not normally distributed the Mann–Whitney U test will be used.
As this is a randomized controlled trial, we expect that randomization in this large study population will sufficiently balance the baseline characteristics. Baseline balance is tested and imbalance compensated in all pre-operative variables and on ARISCAT scores (as mentioned above).14 However if imbalance occurs, the confounding factor will be corrected using a multiple logistic regression model. For this we will treat the proportion as a binary response (complications occur during day one to day five postoperative).
Time to event variables (primary and secondary outcomes) are analysed using a proportional hazard model adjusted for possible imbalances of patients’ baseline characteristics. Time course variables (e.g. repeated measures of vital parameters, blood values, VAS–scores, actual mobility) are analysed by a linear mixed model. The linear mixed models procedure expands the GLM so that the data are permitted to exhibit correlated and non–constant variability. The model includes two factors: 1) study group (fixed factor, intervention or control group), each level of the study group factor can have a different linear effect on the value of the dependent variable; 2) time as a covariate, time is considered to be a random sample from a larger population of values, the effect is not limited to the chosen times.
Study OrganizationThe Executive Committee is constituted of the study principal investigator and the principal investigators of the investigating centres that approved the final trial design and protocol issued
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to the clinical sites and to the Data and Safety Monitoring Board (DSMB).
The independent DSMB watches over the ethics of conducting the study in accordance with the Declaration of Helsinki, monitors patient safety and reviews safety issues as the study progresses. All serious adverse events, and all unexpected and related or possibly–related adverse events will be reported blinded to the appointed international SAE–manager, who assesses the events and reports this information to the DSMB within 24 hours of that event in the case of a serious adverse event or within one week in the case of an adverse event.
The Steering Committee is composed of the principal investigators of the principle participating centres that contribute to the design and revisions of the study protocol.
The National Coordinators are responsible for administrative management and communication with the local principle investigator and provide assistance to the participating clinical sites in trial management, record keeping and data management.
Discussion
It has become clear that mechanical ventilation can attenuate lung damage and may even be the primary factor in lung injury.2,3 ALI/ARDS is characterized by heterogeneous distribution of pulmonary aeration. During ventilation the aerated part of the lung receives the largest part of the tidal volume, potentially causing overdistention with excessive alveolar wall tension and stress. The non–aerated atelectatic lung regions are prone to repeated collapse and re–expansion of alveoli, causing shear stress and diffuse mechanical damage of the alveoli.2,28 This could trigger local and systemic inflammation, which has been suggested to cause ventilator–associated lung injury.1,8,9
Protective mechanical ventilation using lower tidal volumes could reduce ventilator–associated lung injury. Indeed, the use of lower tidal volumes has been found beneficial in patients who needed long–term mechanical ventilation for ALI/ARDS.1,15 Two retrospective studies31,32 and one randomized controlled trial33 suggest lower tidal volumes to be beneficial in patients without acute lung injury in long-term ventilation as well. Other trials suggest that ventilation with lower tidal volumes is also beneficial in short term ventilation for patients without preexisting lung injury.8,9,34 In these trials different levels of PEEP were used, making comparison and interpretation of the additional effect of PEEP difficult.
During general anesthesia reductions in end–expiratory lung volume and increases in airway closure is commonly seen.35 Both contribute to atelectasis formation. The most important morbid postoperative pulmonary complication is atelectasis formation, which increases the risk for pneumonia and hypoxic acute respiratory failure.36 Postoperative pulmonary complications, in particular postoperative respiratory failure, add to the morbidity and mortality of surgical patients.12,13 PEEP prevents alveolar collapse and atelectasis formation. Recruitment manoeuvres can be used to achieve initial alveolar recruitment.3,37 Data suggests that recruitment manoeuvres
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adequately support the beneficial effects of PEEP in short-term ventilation.38,39 However, PEEP levels should not be too high, to avoid overdistention of the lung.1,40
Various studies showed mechanical ventilation according to an open lung concept to improve ventilatory efficacy of the lungs in patients with healthy lungs undergoing general anesthesia.3,37 Studies have shown the open lung concept to attenuate inflammatory responses and to prevent loss of functional residual capacity in cardiac surgery patients.34,41 Of note, there is some controversy about the clinical importance of the cyclic collapse of alveoli. Indeed, the potential of ventilation strategies with lower tidal volumes and PEEP for protecting the lungs during the intraoperative period in patients without previous lung injury has been questioned.6,7
The PROVHILO trial is the first randomized controlled study powered to investigate whether protective mechanical ventilation using higher levels of PEEP complemented by recruitment manoeuvres attenuates postoperative pulmonary complications. The two ventilation strategies used in the PROVHILO trial are composed to match as many clinically applied anesthesia ventilators as possible. With these standardized ventilation strategies, we aim to minimize variation between ventilation strategies used in the participating centres.
The primary endpoint of this trial is a composed endpoint (postoperative pulmonary complications). This could be seen as a shortcoming, since the effect of the intervention on one postoperative pulmonary complication could be diluted if other postoperative pulmonary complications are not affected, or affected to a lesser content. However, since we collect and report on all postoperative pulmonary complications, it may still be possible to determine the effects on separate complications.
The main concern in the statistical interim analysis is not to withhold positive effects of the treatment to the control group. However, to achieve maximal protection for patients and to have a lower chance of achieving positive effects of the intervention on postoperative pulmonary complications if they were not really present, different stopping rules are defined for a strong beneficial effect on postoperative pulmonary complications of the intervention versus a worse effect on postoperative pulmonary complications.
The spectrum of ventilator–associated lung injury does not only include pulmonary inflammation, but also an increase in systemic inflammatory mediators.2,42-44 The lung has been suggested as an important causative part of the inflammation–induced systemic disease state that can evolve to multi organ failure, rather than merely a pulmonary disease process. Alveolar collapse during mechanical ventilation can lead to activation of inflammatory response both locally and systemically, which can play a role in modulating the individual patient’s outcome.3,28,45 To determine this possible effect on patients in this trial, secondary endpoints on extra–pulmonary complications are collected and reported, as well as blood samples for the determination of specific markers of distal organ injury.
Several confounding factors can be suggested. Postoperative pain is a commonly acknowledged contributor to postoperative atelectasis.46,47 Respiratory chest physiotherapy has been shown to decrease postoperative respiratory complications in cardiac surgery, when performed before
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surgery.48 It is still uncertain if postoperative physiotherapeutic procedures are beneficial, although there is some evidence in favour of physiotherapy.47 Excessive intraoperative fluid administration is another possible contributing factor to the development of respiratory failure.49 These factors are not protocolized by the PROVHILO trial. The protocol stresses that general anesthesia, post–operative pain management, physiotherapeutic procedures, fluid management and all other perioperative procedures are to be performed according to the centres’ specific expertise and routine clinical use. We aim to minimize interference with the effect of PEEP and recruitment manoeuvres on postoperative pulmonary complications. Suggestions on the abovementioned perioperative procedures are made in the protocol, to keep the variability as small as possible. No suggestions are made on type of anesthesia to use, to make the trial as accessible as possible for anaesthesiologists. It is known, however, that several anaesthetic drugs affect lung capacity during surgery.50,51 Since we collect and report on all commonly known risk factors for postoperative pulmonary complications and intra-operative administered drugs, it may still be possible to determine the effect on the primary and secondary outcomes.
In conclusion, the PROVHILO trial is a worldwide investigator–initiated randomized controlled trial powered to test the hypothesis that an open lung mechanical ventilation strategy using higher levels of PEEP and recruitment manoeuvres during short term intraoperative mechanical ventilation prevents against post–operative pulmonary complications. The PROVHILO trial also determines the effect of an open lung approach on postoperative extra–pulmonary complications. Finally, in the PROVHILO trial the effect of lung–protective mechanical ventilation is monitored by highly specific biomarkers of lung injury.
Funding Source
This study is an investigator–initiated trial, funded by the Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands, and the European Society of Anesthesiology (ESA).
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7. Wrigge H, Uhlig U, Zinserling J, Behrends-Callsen E, Ottersbach G, Fischer M, Uhlig S, Putensen C. The effects of different ventilatory settings on pulmonary and systemic inflammatory responses during major surgery. Anesth Analg 2004, 98:775-781
8. Choi G, Wolthuis EK, Bresser P, Levi M, van der Poll T, Dzoljic M, Vroom MB, Schultz MJ. Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents alveolar coagulation in patients without lung injury. Anesthesiology 2006, 105:689-695
9. Wolthuis EK, Choi G, Dessing MC, Bresser P, Lutter R, Dzoljic M, van der Poll T, Vroom MB, Hollmann M, Schultz MJ: Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents pulmonary inflammation in patients without preexisting lung injury. Anesthesiology 2008, 108:46-54
10. Rothen HU, Sporre B, Engberg G, Wegenius G, Reber A, Hedenstierna G. Prevention of atelectasis during general anaesthesia. Lancet 1995, 345:1387-1391
11. Jaber S, Coisel Y, Marret E, Malinovsky JM, Bouaziz H. Ventilatory Management during General Anesthesia: A Multicenter Observational Study. Anesthesiology 2006:A1516
12. Arozullah AM, Daley J, Henderson WG, Khuri SF. Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. The National Veterans Administration Surgical Quality Improvement Program. Ann Surg 2000, 232:242-253
13. Smetana GW, Lawrence VA, Cornell JE. Preoperative pulmonary risk stratification for noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern Med 2006, 144:581-595
14. Canet J, Gallart L, Gomar C, Paluzie G, Valles J, Castillo J, Sabate S, Mazo V, Briones Z, Sanchis J. Prediction of Postoperative Pulmonary Complications in a Population based Surgical Cohort. Anesthesiology, 113:1338-1350
15. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. NEJM 2000, 342:1301-1308
16. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981, 123:659-664
18. 2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Part 4: Advanced life support. Resuscitation 2005, 67:213-247
19. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R. Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee. Intensive Care Med 1994, 20:225-232
20. Bone RC. Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA 1992, 268:3452-3455
21. Thygesen K, Alpert JS, White HD, Jaffe AS, Apple FS, Galvani M, Katus HA, Newby LK, Ravkilde J, Chaitman B, et al. Universal definition of myocardial infarction. Circulation 2007, 116:2634-2653
22. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004, 8:R204-212
23. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009, 145:24-33
24. Reintam A, Parm P, Kitus R, Starkopf J, Kern H. Gastrointestinal failure score in critically ill patients: a prospective observational study. Crit Care 2008, 12:R90
25. Levitt JE, Gould MK, Ware LB, Matthay MA. The pathogenetic and prognostic value of biologic markers in acute lung
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injury. J Intensive Care Med 2009, 24:151-16726. Determann RM, Wolthuis EK, Choi G, Bresser P, Bernard A, Lutter R, Schultz MJ. Lung epithelial injury markers are
not influenced by use of lower tidal volumes during elective surgery in patients without preexisting lung injury. Am J Physiol Lung Cell Mol Physiol 2008, 294:L344-350
27. Parsons PE, Eisner MD, Thompson BT, Matthay MA, Ancukiewicz M, Bernard GR, Wheeler AP. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005, 33:1-6
28. Del Sorbo L, Slutsky AS. Ventilatory support for acute respiratory failure: new and ongoing pathophysiological, diagnostic and therapeutic developments. Curr Opin Crit Care, 16:1-7
29. Plotz FB, Slutsky AS, van Vught AJ, Heijnen CJ. Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses. Intensive Care Med 2004, 30:1865-1872
30. Arozullah AM, Khuri SF, Henderson WG, Daley J. Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Ann Intern Med 2001, 135:847-857
31. Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, Rana R, St Sauver JL, Lymp JF, Afessa B, Hubmayr RD. Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 2004, 32:1817-1824
32. Gajic O, Frutos-Vivar F, Esteban A, Hubmayr RD, Anzueto A. Ventilator settings as a risk factor for acute respiratory distress syndrome in mechanically ventilated patients. Intensive Care Med 2005, 31:922-926
33. Determann RM, Royakkers A, Wolthuis EK, Vlaar AP, Choi G, Paulus F, Hofstra JJ, de Graaff MJ, Korevaar JC, Schultz MJ. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care 2010, 14:R1
34. Reis Miranda D, Gommers D, Struijs A, Dekker R, Mekel J, Feelders R, Lachmann B, Bogers AJ. Ventilation according to the open lung concept attenuates pulmonary inflammatory response in cardiac surgery. Eur J Cardiothorac Surg 2005, 28:889-895
35. Pelosi P, Rocco PR. Airway closure: the silent killer of peripheral airways. Crit Care 2007, 11:11436. Pelosi P, Jaber S. Noninvasive respiratory support in the perioperative period. Curr Opin Anaesthesiol, 23:233-23837. Lapinsky SE, Mehta S. Bench-to-bedside review: Recruitment and recruiting maneuvers. Crit Care 2005, 9:60-6538. Girgis K, Hamed H, Khater Y, Kacmarek RM. A decremental PEEP trial identifies the PEEP level that maintains oxygenation
after lung recruitment. Respir Care 2006, 51:1132-113939. Talab HF, Zabani IA, Abdelrahman HS, Bukhari WL, Mamoun I, Ashour MA, Sadeq BB, El Sayed SI. Intraoperative
ventilatory strategies for prevention of pulmonary atelectasis in obese patients undergoing laparoscopic bariatric surgery. Anesth Analg 2009, 109:1511-1516
40. Maisch S, Reissmann H, Fuellekrug B, Weismann D, Rutkowski T, Tusman G, Bohm SH. Compliance and dead space fraction indicate an optimal level of positive end-expiratory pressure after recruitment in anesthetized patients. Anesth Analg 2008, 106:175-181
41. Reis Miranda D, Struijs A, Koetsier P, van Thiel R, Schepp R, Hop W, Klein J, Lachmann B, Bogers AJ, Gommers D. Open lung ventilation improves functional residual capacity after extubation in cardiac surgery. Crit Care Med 2005, 33:2253-2258
42. Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 1998, 157:1721-1725
43. Imai Y, Parodo J, Kajikawa O, de Perrot M, Fischer S, Edwards V, Cutz E, Liu M, Keshavjee S, Martin TR, et al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 2003, 289:2104-2112
44. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998, 157:294-323
45. Papadakos PJ. Cytokines, genes, and ARDS. Chest 2002, 121:1391-139246. Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan JA, Jr., Wu CL. Efficacy of postoperative epidural analgesia: a
metaanalysis. JAMA 2003, 290:2455-246347. Ferreyra G, Long Y, Ranieri VM. Respiratory complications after major surgery. Curr Opin Crit Care 2009, 15:342-34848. Filsoufi F, Rahmanian PB, Castillo JG, Chikwe J, Adams DH. Predictors and early and late outcomes of respiratory failure
in contemporary cardiac surgery. Chest 2008, 133:713-72149. Fernandez-Perez ER, Keegan MT, Brown DR, Hubmayr RD, Gajic O. Intraoperative tidal volume as a risk factor for
respiratory failure after pneumonectomy. Anesthesiology 2006, 105:14-1850. Chawla G, Drummond GB. Fentanyl decreases end-expiratory lung volume in patients anaesthetized with sevoflurane.
Br J Anaesth 2008, 100:411-41451. Hedenstierna G, Edmark L: The effects of anesthesia and muscle paralysis on the respiratory system. Intensive Care
Med 2005, 31:1327-1335
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Chapter 8
High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial
Hemmes SNT, Gama de Abreu M, Pelosi P, Schultz MJ for the PROVE Network Investigators for the Clinical Trial Network of the European Society of AnaesthesiologyLancet 2014; 9; 384(9942):495-503
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Abstract
Background. The role of positive end–expiratory pressure (PEEP) in mechanical ventilation during general anaesthesia for surgery remains uncertain. Higher PEEP levels may protect against postoperative pulmonary complications (PPCs), but could also cause intra–operative circulatory depression and lung injury from overdistension. We tested the hypothesis that higher PEEP plus recruitment manoeuvres protects against PPCs in patients at risk for PPCs receiving mechanical ventilation with lower tidal volumes during general anaesthesia for open abdominal surgery.
Methods. In this international, randomized controlled trial in 30 centres we allocated 900 patients at risk for PPCs planned for open abdominal surgery under general anaesthesia and ventilation at tidal volumes of 8 ml/kg to higher PEEP (12 cmH2O) with recruitment manoeuvres or lower PEEP (≤ 2 cmH2O) without recruitment manoeuvres, using a centralized computer-generated randomization system. Patients and outcome assessors were blinded for the intervention. Primary endpoint was a composite of PPCs by postoperative day five. The study is registered at Controlled-Trials.gov, number ISRCTN70332574.
Findings. From February 2011 through January 2013, 447 patients were randomized to the higher PEEP and 453 to the lower PEEP group. Six patients were excluded from analysis: 4 withdrew consent, 2 violated inclusion criteria. Median PEEP levels were 12 [12–12] and 2 [0–2] cmH2O in the higher and lower PEEP group, respectively. PPCs occurred in 174 of 445 patients (40%) in the higher PEEP group and in 172 of 449 patients (39%) in the lower PEEP group (relative risk, 1.01; 95% CI 0.86–1.20; P = 0.86). In the higher PEEP group, patients developed intraoperative hypotension and needed more vasoactive drugs.
Interpretation. A strategy with higher PEEP plus recruitment manoeuvres during open abdominal surgery does not protect against PPCs.
Funding. Funded by the Academic Medical Center, Amsterdam, The Netherlands, and the European Society of Anaesthesiology.
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Introduction
Postoperative pulmonary complications (PPCs) are at least as frequent as cardiac complications during non–cardiac surgery.1 PPCs increase mortality after open abdominal surgery.2,3 It is gradually more recognized that mechanical ventilation may influence the incidence of PPCs4 and even distal organ dysfunction.5 Different mechanisms have been proposed to explain the injurious effects of ventilation. Both hyperinflation and repetitive tidal recruitment of lung units can induce the release of pro–inflammatory mediators, leading to lung and distal organ injury.6
Prevention of hyperinflation by use of lower tidal volumes (VTs) reduces mortality in patients with the acute respiratory distress syndrome (ARDS).7 Prevention of repetitive tidal recruitment by use of higher positive end–expiratory pressure (PEEP) is also associated with reduced mortality in these patients, but only when ARDS is severe.8 Several studies suggest that use of lower VTs in patients without lung injury under general anaesthesia may also reduce the incidence of PPCs.4 This hypothesis was recently confirmed in one single–centre9 and one national multicentre trial.10 However, in both trials, the use of lower VTs was combined with higher PEEP, thus it is unclear whether beneficial effects came from prevention of hyperinflation or prevention of repetitive tidal recruitment. While it is argued that use of too low PEEP could lead to atelectasis with ventilation strategies that use lower VTs,6,11 higher PEEP could also provoke complications including intraoperative circulatory depression12 and even promote hyperinflation.13
We conducted the PROtective Ventilation using HIgh versus LOw PEEP (PROVHILO) trial to test the hypothesis that a ventilation strategy with higher levels of PEEP plus recruitment manoeuvres during general anaesthesia for open abdominal surgery protects against PPCs in patients at risk for PPCs.
Methods
The PROVHILO trial was an investigator–initiated, international, multicentre, double–blind, parallel randomized controlled two–arm trial. The study protocol and the statistical analysis plan were approved by the Institutional Review Boards of the Academic Medical Center (AMC), Amsterdam, The Netherlands, as well as of all participating centres and published both in TRIALS14 and Controlled Trials.gov, number ISRCTN70332574. The steering committee was responsible for accuracy and completeness of fidelity of the study to the protocol, the collected data and data analyses. The writing committee drafted the manuscript without editorial assistance and all authors provided revisions and comments.
An independent data safety and monitoring board oversaw conduct of the trial, safety of the participants, and interpreted blind interim analysis results. A random sample of 6 centres was visited on site by an independent monitor to assess protocol adherence. There was no industry support or involvement for the PROVHILO trial.
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PatientsPatients were screened and randomized from February 2011 to January 2013 at 30 hospitals in ten countries. Participating hospitals are listed in the Supplementary Appendix. Written informed consent was obtained from all participating patients before randomization. We considered adults scheduled for open abdominal surgery under general anaesthesia. Enrolment was restricted to patients who had an intermediate or high risk of experiencing PPCs.3 Patients who were planned for laparoscopic surgery, were pregnant (excluded by laboratory analysis), had a body mass index > 40 kg/m2, had severe cardio– or pulmonary comorbidities or another condition that may have compromised safe trial procedure, or who had consented for another interventional study or declined to participate, were excluded from study participation. The full inclusion and exclusion criteria are presented in tables S1 and S2 in the Supplementary Appendix.
Randomization and maskingPatients were assigned to their study group in random blocks of four and stratified per centre. Local investigators randomized patients after inclusion of the patients, using a secured, centralized, computer–generated and web–based, randomization system. In each centre at least two investigators were involved: one who was aware of the allocated intervention and collected intraoperative data; the other remained blinded to the intraoperative interventions and evaluated the outcomes, scoring postoperative pulmonary and extrapulmonary complications. The allocation was also concealed from patients, research staff, the independent statistician, and the data safety and monitoring board. Data were collected on paper case report forms and transcribed by local investigators onto secure web–based electronic case report forms (OpenClinica, Boston, MA, USA).
InterventionsPatients were randomized to receive intraoperative ventilation using either a higher PEEP strategy, with PEEP of 12 cmH2O plus recruitment manoeuvres, or a lower PEEP strategy, with PEEP of ≤ 2 cmH2O without recruitment manoeuvres. In the higher PEEP group, recruitment manoeuvres with an incremental tidal volume strategy were performed directly after induction of anaesthesia, after any disconnection from the ventilator, and just before tracheal extubation (see table S3 for details). A rescue strategy was designated for patients in whom pulse oximetry (SpO2) decreased to < 90% without evidence of airway problems, severe hemodynamic impairment, or ventilator malfunction. The strategy included a stepwise increase of inspired oxygen (FIO2), progressive increase in PEEP and recruitment manoeuvres (table S3). It was sequentially implemented to return SpO2 to ≥ 92%.
Patients were ventilated using a volume–assist mode during surgery, and optionally switched to pressure support mode near the end of surgery. VTs were set at 8 ml/kg predicted body weight. FIO2 was set at 0.40 or higher to a target SpO2 ≥ 92%. The respiratory rate was adjusted to maintain end–tidal CO2 (FE’CO2) between 35 and 45 mmHg. The inspiration–to–expiration ratio was 1:2. Anaesthesiologists were allowed to change the ventilator settings upon the surgeon’s request, or if there was any concern about patient’s safety. Safety concerns potentially included low systemic blood pressure unresponsive to intravenous fluids and/or vasoactive drugs, new arrhythmias not responding to treatment, or a need for massive transfusion. Other aspects of general anaesthesia, fluid administration, and pain management were per routine.
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OutcomesA collapsed composite of PPCs was chosen as the primary endpoint. PPCs occurring within the first five postoperative days included hypoxemia, severe hypoxemia, bronchospasm, suspected pulmonary infection, pulmonary infiltrate, aspiration pneumonitis, development of ARDS, atelectasis, pleural effusion, pulmonary oedema caused by cardiac failure and pneumothorax. Definitions are presented in table S4.
Intraoperative complications served as secondary and safety endpoints, and included SpO2 < 90% requiring rescue, hypotension (systolic arterial blood pressure < 90 mmHg for more than 3 minutes), any need for vasoactive medication, any new arrhythmias requiring intervention, massive transfusion (> 5 units of packed red blood cells during one hour), and any surgical complication. Postoperative extrapulmonary complications included development of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis or septic shock, extrapulmonary infection, coma, acute myocardial infarction, acute renal failure, disseminated intravascular coagulation, hepatic failure, gastro–intestinal bleeding, gastro–intestinal failure, and impaired wound healing (definitions are presented in table S5).
Patients were assessed daily, scoring clinical data, the presence of the predefined outcomes, and need for intensive care unit admission or readmission until the fifth postoperative day, and shortly before hospital discharge. Ninety days after surgery, we determined the number of hospital–free days (including admissions to other hospitals) and vital status.
Statistical analysisWe calculated that a sample size of 900 patients would provide a power of 80% to detect a difference between the incidences of PPCs with lower PEEP (24%) and higher PEEP (16.5%).1,3,9,15,16 An independent data safety and monitoring board conducted an interim analysis after enrolment of the first 300 and 600 patients, according to the a priori statistical analysis plan. The Board did not recommend trial discontinuation after either interim analysis and 900 patients were therefore included. All patients were analysed under intention–to–treat rules.
Postoperative variables were compared using Student’s t–test or Mann–Whitney U test for continuous variables depending on the characteristics of the variables and chi-square test for categorical variables. The composite primary outcome, total occurrence of PPCs, and the secondary outcome of total occurrence of extrapulmonary complications, both in the first five postoperative days, were compared using an unadjusted chi–square test weighing each individual complication equally. The primary endpoint was not adjusted for baseline imbalance. Due to the two interim analyses a two–sided alpha level of 0.045 was considered statistically significant for the primary endpoint. Statistical significance for other variables was accepted at a P–value < 0.05. Where appropriate, statistical uncertainty was expressed by 95% confidence levels. Kaplan–Meier estimates of survival curves were calculated; log–rank tests were used to compare survival distributions between the lower and higher PEEP group. Data used for the Kaplan–Meier estimates was censored when patients did not experience a PPC during the study period, or when patients were lost to follow up before the end of day five. A post–hoc analysis was performed on the primary endpoint, discarding hypoxemia from the composite endpoint of PPCs. Further exploratory post–hoc analyses included a per–protocol analysis in which patients
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of the higher PEEP group who did not receive higher PEEP throughout the procedure and all RMs as indicated by the study protocol were analysed as patients in the lower PEEP group, and the association between the incidence of postoperative complications was analysed; intra–operative use of medication (anaesthetics, neuromuscular blocking agents, and opioids); the net effect of the treatment group (higher PEEP) on the primary endpoint (PPCs), controlling for centre; and a multiple logistic regression analysis to identify baseline and intra–operative covariates associated with PPCs.
Analyses were performed using R (version 2.3; R Foundation for Statistical Computing, Vienna, Austria).
Role of funding sourceThe European Society of Anaesthesiology (ESA) and the Academic Medical Center (AMC), Amsterdam, The Netherlands financially supported and endorsed the trial. They had no influence on trial design, conduct of the trial, data analysis, or reporting.
Results
From February 2011 through January 2013, we enrolled 900 patients in 30 centres in Europe and the U.S.A. Randomization of patients was balanced within centres; 447 patients were assigned to ventilation with higher PEEP; 453 patients were assigned to ventilation with lower PEEP. Six randomized patients were excluded from analysis. Six patients receiving other treatment than allocated were kept in their original randomization arms (figure 1). Data for the primary endpoint could be analysed for 445 patients in the higher PEEP group and 449 patients in the lower PEEP group. Surgery was for cancer in 268 (61%) of the higher PEEP patients and 281 (63%) in the lower PEEP patients.
Median VT was similar between groups and remained within target throughout intra-operative mechanical ventilation. Median PEEP levels were 12 [12–12] cmH2O in the higher PEEP group and 2 [0–2] cmH2O in the lower PEEP group. The percentage of patients receiving recruitment manoeuvres following intubation was 99% in the higher PEEP group and 1% in the lower PEEP group; 85% of patients in the higher PEEP group and 0.7% in the lower PEEP group received recruitment manoeuvres before extubation (for details, see table S6). Peak pressures and dynamic respiratory compliance were significantly higher in the higher PEEP group. SpO2 levels were only marginally but statistically significantly higher in the higher PEEP group. In the higher PEEP group 2% of the patients needed a rescue for desaturation versus 8% of patients in the lower PEEP group (P < 0.0008, table 3). Details on the duration of the rescue strategy and highest step reached are described in table S7. In 34 patients in the higher PEEP group, PEEP was decreased on request of the surgeon (5 cases) or the attending anaesthesiologist (3 cases); because of hypotension (14 cases), massive surgical bleeding (10 cases), or for other reasons (2 cases).
Hemodynamic compromise and use of vasopressors occurred more frequently during the higher PEEP strategy (table 3), and these patients received more fluids (table 2). There were
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Figure 2. The probability of the composite primary endpoint of postoperative pulmonarycomplications by postoperative day five between the higher PEEP group (straight line) and the lower PEEP group (dotted line) as presented by a Kaplan–Meier graph (P = 0.89, log–rank test)
Figure 1. Randomization and follow–up of study patientsNine hundred patients were randomly assigned to a study group to obtain the full sample size. Four patients withdrew informed consent for the use of their data after the end of the study intervention. One patient was randomized twice and therefore violated the exclusion criteria. One patient was randomized, but did not receive study intervention
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Table 1. Baseline characteristics of patients
Variable Higher PEEP N = 445
Lower PEEP N = 449
Male sex – % (n/N) 58 (259/445) 57 (255/449)
Age – year, median [IQR] 65 [54 - 73] 66 [56 - 74]
BMI m2, mean (sd) 25.5 (4.2) 25.6 (4.4)
Body Weight – kg, mean (sd) 72.5 (14.3) 72.7 (14.8)
mixed (volatile and intravenous) 91 (404/444) 91 (408/448)
Epidural – % (n/N) 49 (219/445) 50 (226/449)
thoracic 79 (173/218) 77 (174/226)
lumbar 21 (46/219) 23 (52/226)
Data is presented as: means (sd), median [IQR] or proportion % (n/N); n: number of patients; N: total patients; BMI: Body Mass Index, calculated as weight (kg)/ height (m)2 = kg/m2; kg: kilogram; m: meters; ASA: American Society of Anesthesiology; COPD: Chronic Obstructive Pulmonary Disease; Inhalation therapy for COPD: inhaled bronchodilators and/or steroids’ SpO2: oxyhaemoglobin saturation measured by pulse oximeter; †Duration of surgery is the time between skin incision and closure of the incision
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no differences in duration of surgery, administered anaesthetics, use of epidural anaesthesia, intra–operative blood loss, transfusion of blood products, arrhythmias, surgical complications, or urine output (table 1, 2, 3, S8 and S9).
PPCs within the initial five postoperative days occurred in 174 (40%) patients in the higher PEEP group versus 172 (39%) patients in the lower PEEP group (relative risk, 1.01; 95% confidence interval 0.85–1.20; P = 0.84) (table 3 and figure 2). The need for continued or new postoperative mechanical ventilation did not differ significantly between groups: 18 (4%) patients in the higher PEEP group versus 24 (5%) patients in the lower PEEP group. Hypoxemia was relatively common at 24% in the higher PEEP group and 21% in the lower PEEP group. Discarding hypoxemia from the composite endpoint of PPCs did not result in a difference between groups (table 3). There was no heterogeneity in PPCs across centres.
In the higher PEEP group, 244 (55%) patients developed extrapulmonary complications versus 242 (54%) patients in the lower PEEP group (P = 0.78) (table 3 and figure S2). Gastro–intestinal failure was the most common extrapulmonary complication, followed by SIRS and acute renal failure, but distributed equally between randomization groups (table 3).
There was no difference in the need for intensive care unit admission, number of hospital free days at postoperative day 90, nor in hospital mortality (table 3).
The results of a per–protocol analysis were not different from the intention–to–treat analysis (table S10). The results of the post–hoc analysis of the association between the incidence of postoperative pulmonary complications and intra–operative use of medication (anaesthetics, neuromuscular blocking agents, and opioids), and a multiple logistic regression analysis to identify baseline and intra–operative covariates, which are associated with PPCs are shown in the Supplementary Appendix (tables S9 and S11).
Discussion
PROVHILO is the first trial in which identical lower VTs were used in both study arms, making it possible to isolate the effects of higher PEEP levels from the known effects of VT size. In 900 patients at risk for PPCs after mechanical ventilation under general anaesthesia for open abdominal surgery, the incidence of PPCs within the first five postoperative days was comparable between patients receiving higher PEEP with recruitment manoeuvres and lower PEEP without recruitment manoeuvres.
Our composite endpoint of PPCs included hypoxemia, which was the most common PPC. Restricting our analysis to more severe PPCs did not change the study results, suggesting that PEEP level does not alter the risk of more severe pulmonary complications. The incidence of PPCs in the present trial was substantially higher than in these previous investigations,1,3,9,15,16 which could have been caused by the much higher risk of developing PPC’s as compared to patients in previous studies. Because the observed incidence was so high, our trial had sufficient statistical
power to detect a difference in the incidence of PPCs of 7.5%. We made efforts to minimize the risk of bias through centralized randomization, and blinding of study group assignment for outcome assessors. We used a relevant composite outcome at a meaningful interval in this surgical population. In addition, we published the statistical analysis plan before unblinding study group assignments.14
The chosen PEEP level in the higher PEEP group is supported by the literature.17,18 Previous studies tested PEEP levels of 10 cmH2O during intra–operative ventilation,19-21 but atelectasis persisted during anaesthesia in some patients, especially when higher FIO2 was used.21 Notably, these atelectasis may also persist in the first postoperative days, especially after abdominal surgery.22
Temperature at end of surgery – ⁰C, mean (sd) 36 (0.6) 36 (0.6) 0.58
Perforation organ – % (n/N) 0.9 (4/444) 0.9 (4/444) 1
Data is presented as means (sd); median [IQR] or proportion % (n/N); n: number of patients; N: total patients; PBW: predicted body weight, calculated as: 50 + 0.91 x (centimetres of height – 152.4) for males and 45.5 + 0.91 x (centimetres of height – 152.4) for females; #Begin: during the first hour of mechanical ventilation; End: during the last hour before extubation; PEEP: positive end-expiratory pressure; Cdyn: calculated dynamic respiratory compliance, calculated as VT/ (Ppeak – PEEP) = mL/cmH2O; Ppeak: peak pressure; FiO2: fraction inspired oxygen; SpO2: Oxyhaemoglobin saturation measured by pulse oximeter; FE’CO2: expiratory carbon dioxide partial pressure; BP: blood pressure; HR: heart rate; bpm: beats per minute; RM: recruitment manoeuvre; PRBC: packed red blood cells; FFP: fresh frozen plasma; ⁰C = degrees Celsius; *Categories of FiO2 and BPmean are scored upon occurrence of worst clinical parameter (no., %) $Total fluids are crystalloids and colloids
Data is presented as means ± (sd), median [IQR] or proportion % (n/N); n: number of patients; N: total patients and relative risk with 95% Confidence Intervals; PPCs: postoperative pulmonary complications; ARDS: acute respiratory distress syndrome; SIRS: systemic inflammatory response syndrome; Renal failure documented as follows: Risk: increased creatinine x1.5 or glomerular filtration rate (GFR) decrease > 25% or urine output (UO) < 0.5 ml/kg/h x 6 h; Injury: increased creatinine x2 or GFR decrease > 50% or UO < 0.5 ml/kg/h x 12 hr; Failure: increase creatinine x3 or GFR decrease > 75% or UO < 0.3 ml/kg/h x 24 hr or anuria x 12 hrs; Loss: persistent ARF = complete loss of kidney function > 4 weeks; Gastro-intestinal failure score: 0 = normal gastrointestinal function; 1 = enteral feeding with under 50% of calculated needs or no feeding 3 days after abdominal surgery; 2 = food intolerance (FI) or intra–abdominal hypertension (IAH); 3 = FI and IAH; and 4 = abdominal compartment syndrome; Impaired wound healing is defined as an interruption in the timely and predictable recovery of mechanical integrity in the injured tissue; MV: mechanical ventilation; ICU: intensive care unit*Pulmonary complications, and extrapulmonary complications and impaired wound healing on day 1 to 5 were scored YES as soon as an event occurred; **Acute Renal failure & Gastro-intestinal failure; highest value occurring in day 1 to 5 is scored; ŦIntra-operative complications were scored YES as soon as complication occurred; Rescue strategy for desaturation (SpO2 < 90%) performed as described in methods; Hypotension defined as systolic arterial blood pressure < 90 mmHg for more than 3 minutes; Vasoactive drugs defined as need for vasoactive medication; New arrhythmias requiring intervention
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We chose a PEEP level of 12 cmH2O to maximize lung opening throughout mechanical ventilation, irrespective of FIO2. The higher PEEP strategy resulted in improved dynamic compliance of the respiratory system compared to the lower PEEP group, suggesting higher alveolar recruitment.
The results of the present trial expand the understanding of findings of two recently published trials comparing a conventional ventilation strategy with higher VTs and no PEEP with a protective strategy using lower VTs and higher levels of PEEP in similar patient populations.9,10 It is suggested that benefit of protective ventilation in those trials must have come from the higher levels of PEEP.23 However, the design of those trials does not allow identifying whether lower VTs, higher levels of PEEP, or both, are responsible for the beneficial effects. The results of the present trial challenge the hypothesis that higher PEEP is responsible for the beneficial effects of protective ventilation. However, it must be kept in mind that trials are not completely comparable, as the levels of higher PEEP in the previous trials9,10 were approximately 4 – 6 cmH2O lower than those in the present trial.
Perhaps in our trial, higher PEEP stabilized the lungs and protected against lung injury from tidal recruitment, but the adverse effects counteracted the possible beneficial effects. Peak airway pressures were increased in the higher PEEP group, possibly causing hyperinflation in non–dependent lung zones. Furthermore, higher PEEP further impaired the hemodynamics. Thus, our findings suggest that levels of PEEP higher than recommended in previous trials,9,10 although improving the elastic properties of the respiratory system does not enhance lung protection in general anaesthesia.
Several drugs used for general anaesthesia induce peripheral vascular smooth muscle relaxation, decrease the arterial pressure, and even impair cardiac contractility.24,25 Also, epidural anaesthesia, which is frequently used in combination with general anaesthesia during open abdominal surgery in up to 50% of cases, may contribute to reduce the peripheral vascular smooth muscle tonus and promote peripheral blood pooling.26 However, there was neither difference in the administration of drugs for general anaesthesia, nor in use of epidural anaesthesia between the groups. The increased incidence of intra–operative hemodynamic adverse events in the higher PEEP group, especially arterial hypotension, thus may have been associated with a reduction of the venous return due to increased intrathoracic with higher PEEP and/or recruitment manoeuvres. Even though those events were limited and responded to increased intravascular volume expansion, as well as use of vasoactive drugs, they might be threatening in presence of ischemic cardiac disease.27
We did not include patients having laparoscopic surgery or morbidly obese patients, both groups that may have especially benefited from higher intra–operative PEEP. Furthermore, we recommended but did not reinforce use of international guidelines and standards for intra–operative and postoperative fluid administration, use of inotropes and/or vasopressors, and use and/or reversal of neuromuscular blocking agents. Our study was pragmatic in its design, rather than tightly controlled. As randomization was balanced within the centres, thus we consider it unlikely that this affected the trial results. As randomization was balanced within the centres, it is unlikely to have affected our results. A corollary is that our results are relatively generalizable to a broad range of practice styles. A corollary is that our results are relatively generalizable
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to a broad range of practice styles. The use of an equally weighed composite endpoint could be seen as a limitation as well, but we have given insight into the distribution of the events by presenting the incidence of each complication separately.
In conclusion, during mechanical ventilation with protective lower VT in patients undergoing open abdominal surgery, the use of higher levels of PEEP and recruitment manoeuvres does not reduce the incidence of PPCs, and more frequently results in hemodynamic instability, as compared to lower PEEP without recruitment manoeuvres.
Panel: Research in context
Systematic reviewApproximately 234 million major surgical procedures are performed worldwide every year, with major impact on the global economy. Among these interventions, around 2.6 million represent high–risk procedures, with 1.3 million patients developing complications that result in 315,000 in–hospital deaths.28 Postoperative pulmonary complications (PPCs) are frequent during non-cardiac surgery and associated with increased risk of in-hospital death, especially after open abdominal surgery.2,3 Notably, the ventilatory strategy applied to these patients may impact outcomes. A recent metaanalysis showed namely that lower tidal volume ventilation is associated with reduced pulmonary and extrapulmonary complications, as well as lower mortality in patients without previous lung injury.4 Also, another metaanalysis showed that mechanical ventilation during general anaesthesia with lower tidal volume and higher positive end-expiratory pressure (PEEP) plus recruitment manoeuvres are associated with lower incidence of PPCs and improved respiratory function when compared to higher tidal volumes and lower PEEP.29 Two recently published trials showed that using lower tidal volumes and higher levels of PEEP with recruitment manoeuvres prevents PPCs and reduces healthcare resources in abdominal surgery.9,10 Nevertheless, clinical evidence so far does not allow determining whether intra-operative use of higher levels of PEEP or use of lower tidal volumes or both are responsible for protection against PPCs. We thus investigated the potential of higher PEEP with recruitment manoeuvres versus lower PEEP to protect against PPCs in 900 patients undergoing general anaesthesia for open abdominal surgery and mechanical ventilation with low tidal volume.
InterpretationAs far as we are aware, this is the largest multicentre, international, randomized controlled trial of mechanical ventilation during general anaesthesia for open abdominal surgery investigating the isolated role of higher PEEP plus recruitment manoeuvres against PPCs. We found that a strategy using higher levels of PEEP and recruitment manoeuvres as compared to lower levels of PEEP without recruitment manoeuvres does not reduce the incidence of PPCs, while increasing intra-operative circulatory impairment. These findings may change current practice of mechanical ventilation during general anaesthesia for open abdominal surgery.
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in a Population-based Surgical Cohort. Anesthesiology 2010; 113: 1338-504. Serpa Neto A, Cardoso SO, Manetta JA, Pereira VG, Esposito DC, Pasqualucci Mde O, et al. Association between use of
lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA 2012; 308: 1651-9
5. Lellouche F, Dionne S, Simard S, Bussieres J, Dagenais F. High tidal volumes in mechanically ventilated patients increase organ dysfunction after cardiac surgery. Anesthesiology 2012; 116: 1072-82
6. Duggan M, Kavanagh BP. Pulmonary atelectasis: a pathogenic perioperative entity. Anesthesiology 2005; 102: 838-547. Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P. Metaanalysis: ventilation strategies and outcomes of the
acute respiratory distress syndrome and acute lung injury. Annals of internal medicine 2009; 151: 566-768. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, et al. Higher vs lower positive end-expiratory pressure
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9. Severgnini P, Selmo G, Lanza C, Chiesa A, Frigerio A, Bacuzzi A, et al. Protective Mechanical Ventilation during General Anesthesia for Open Abdominal Surgery Improves Postoperative Pulmonary Function. Anesthesiology 2013; 118: 1307-21
10. Futier E, Constantin JM, Paugam-Burtz C, Pascal J, Eurin M, Neuschwander A, et al. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. NEJM 2013; 369: 428-37
11. Halter JM, Steinberg JM, Schiller HJ, DaSilva M, Gatto LA, Landas S, et al. Positive end-expiratory pressure after a recruitment maneuver prevents both alveolar collapse and recruitment/derecruitment. American journal of respiratory and critical care medicine 2003; 167: 1620-6
12. Nielsen J, Ostergaard M, Kjaergaard J, Tingleff J, Berthelsen PG, Nygard E, et al. Lung recruitment maneuver depresses central hemodynamics in patients following cardiac surgery. Intensive Care Medicine 2005; 31: 1189-94
13. Carvalho AR, Pacheco SA, de Souza Rocha PV, Bergamini BC, Paula LF, Jandre FC, et al. Detection of tidal recruitment/overdistension in lung-healthy mechanically ventilated patients under general anesthesia. Anesthesia and Analgesia 2013; 116: 677-84
14. Hemmes SN, Severgnini P, Jaber S, Canet J, Wrigge H, Hiesmayr M, et al. Rationale and study design of PROVHILO - a worldwide multicenter randomized controlled trial on protective ventilation during general anesthesia for open abdominal surgery. Trials 2011; 12: 111
15. Arozullah AM, Daley J, Henderson WG, Khuri SF. Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. The National Veterans Administration Surgical Quality Improvement Program. Ann Surg 2000; 232: 242-53
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17. Tusman G, Bohm SH, Vazquez de Anda GF, do Campo JL, Lachmann B. ‘Alveolar recruitment strategy’ improves arterial oxygenation during general anaesthesia. British journal of anaesthesia 1999; 82: 8-13
18. Tusman G, Belda JF. Treatment of anesthesia-induced lung collapse with lung recruitment maneuvers. Current Anaesthesia & Critical Care 2010; 21: 244-9
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22. Lindberg P, Gunnarsson L, Tokics L, Secher E, Lundquist H, Brismar B, et al. Atelectasis and lung function in the postoperative period. Acta Anaesthesiologica Scandinavica 1992; 36: 546-53
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24. Pagel P, Farber N, Pratt P, Warltier D. Cardiovascular Pharmacology. In: Miller R, Eriksson L, Fleisher L, Wiener-Kronish J, Young W, ed. Miller’s Anesthesia. 7th ed. Philadelphia, PA: Elsevier, 2009: 595-632
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27. Luecke T, Pelosi P. Clinical review: Positive end-expiratory pressure and cardiac output. Critical Care 2005; 9: 607-2128. Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR, et al. An estimation of the global volume
of surgery: a modelling strategy based on available data. Lancet 2008; 372: 139-4429. Hemmes SN, Serpa Neto A, Schultz MJ. Intraoperative ventilatory strategies to prevent postoperative pulmonary
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Supplementary Appendix to ‘Higher versus lower positive end-expiratory pressure during general anaesthesia for open abdominal surgery – The PROVHILO trial’
List of PROVE Network InvestigatorsWriting committeeSabrine N.T. Hemmes (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands); Marcelo Gama de Abreu (University Hospital Dresden, Germany); Paolo Pelosi (University of Genoa, Genoa, Italy); Marcus J. Schultz (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands)
Steering committeeSabrine N.T. Hemmes (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands); Paolo Severgnini (University of Insubria, Varese, Italy); Samir Jaber (Saint Eloi University Hospital, Montpellier, France); Jaume Canet (Hospital Universitari Germans Trias I Pujol, Barcelona, Spain); Hermann Wrigge (University of Leipzig, Germany); Michael Hiesmayr (Medical University, Vienna, Austria); Werner Schmid (Medical University, Vienna, Austria); Markus W. Hollmann (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands); Jan M. Binnekade (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands); Göran Hedenstierna (University Hospital, Uppsala, Sweden); Christian Putensen (University Hospital, Bonn, Germany); Marcelo Gama de Abreu (University Hospital Dresden, Germany); Paolo Pelosi (University of Genoa, Genoa, Italy); Marcus J. Schultz (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands)
StatisticianJan M. Binnekade (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands)Data safety and monitoring boardDaniel I. Sessler (chair) (Michael Cudahy Professor & Chair, Department of Outcomes Research, Cleveland Clinic, Cleveland, U.S.A.), Burkhard Lachmann (Professor emeritus, Department of Anaesthesia and Intensive Care Medicine at the Universitätsmedizin Berlin, Charite; Campus Virchow Klinikum, Germany), Robert M. Kacmarek (Professor of Anesthesiology, Harvard Medical School and Director Respiratory Care, Massachusetts General Hospital, Boston, MA, U.S.A.) and Arthur S. Slutsky (Professor at St. Michaels Hospital, University of Toronto, Toronto, ON, Canada and Keenan Research Center of the Li Ka Shing Institute of St. Michael’s Hospital, Toronto)
PROVE Network websitewww.provenet.eu
PROVE Network Collaborators (*, indicates local principal investigator; names are listed in alphabetical order)
AustriaMedical University Vienna: Werner Schmid (national coordinator)*
BelgiumGhent University Hospital: Luc De Baerdemaeker, Stefan De Hert (national coordinator)*, Bjorn Heyse, Jurgen Van LimmenAZ St Jan, Brugge: Jan–Paul Mulier*ZNA Middelheim, Antwerpen: David Velghe*Virga Jesse Ziekenhuis, Hasselt: Luc Jamaer*, Jeroen Vandenbrande Republic of Chile Hospital Clínico de la Pontificia Universidad Católica de Chile, Santiago: Guillermo Bugedo (national coordinator)*, Jorge Florez
CroatiaUniversity Hospital Sveti Duh, Zagreb: Tatjana Goranović, Branka Mazul–Sunko (national coordinator)*
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GermanyUniversity Hospital Dresden: Thomas Bluth, Marcelo Gama de Abreu (national coordinator)*, Andreas Güldner, Thomas Kiss, Thea Koch, Peter Markus Spieth, Christopher Uhlig, Jonathan YaqubDüsseldorf University Hospital, Heinrich-Heine University Düsseldorf: Bea Bastin, Johann Geib, Maximilian S. Schaefer, Martin Weiss, Tanja A. Treschan*University of Leipzig: Andreas W. Reske, Philipp Simon, Hermann Wrigge* Johannes Gutenberg - Universität Mainz: Alexander Brodhun Marion Ferner, Eric Hartmann, Rita Laufenberg-Feldmann*, Lydia StrysUniversity Hospital of Bonn Medical School: Christian Putensen*
ItalyUniversity of Napoli Federico II, Naples: Edoardo De Robertis (national coordinator)* Università degli Studi di Roma Cattolica: Valter Perilli, Rodolfo Proietti*University “Magna Graecia” of Catanzaro: Bruno Amantea, Santo Caroleo*, Francesco TropeaUniversity of Insubria - Azienda Ospedaliera Fondazione Macchi - Ospedale di Circolo - Varese: Alessandro Bacuzzi, Paolo Severgnini*, Massimo VanoniUniversity of Foggia: Gilda Cinnella*, Girolamo Caggianelli, Davide D’Antini, Daniela La Bella, Giuseppina MollicaUniversità degli Studi di Palermo: Andrea Cortegiani, Antonino Giarratano*, Francesca Montalto, Santi Maurizio RaineriAzienda Sanitaria Locale TO3 - Ospedale di Rivoli, Torino: Bruno Barberis, Cristian Celentano, Michele Grio, Luigi Spagnolo*Università degli Studi di Genova: Angelo Gratarola, Alexandre Molin*, Giulia Pellerano, Stefano Pezzato, Roberta Rusca Università degli Studi di Udine: Giorgio Della Rocca*
The NetherlandsAcademic Medical Center, University of Amsterdam: Lieuwe D.J. Bos, Sabrine N.T. Hemmes (national coordinator), Markus W. Hollmann, Marcus J. Schultz*
SpainHospital Universitari Germans Trias I Pujol, Barcelona: Andrea Brunelli*, Agnes MartiHospital Sant Pau, Barcelona: Virginia Cegarra, Alfred Merten, Mª Victoria Moral, Ana Parera, Mª Carmen Unzueta*Fundación Puigvert, Barcelona: Sergi Sabate*, Pilar Sierra, Juan F Mayoral, Mercè PrietoConsorcio Hospital General Universitario Valencia: Manuel Granell Gil*, Conrado Minguez Marín
United KingdomSheffield Teaching Hospitals: Gary H. Mills (national coordinator)*Barts Health NHS Trust, London: Phoebe Bodger*
United States of AmericaMassachusetts General Hospital, Boston: Marcos F. Vidal Melo (national coordinator)*, Demet SulemanjiMayo Clinic, Rochester, Minnesota: Juraj Sprung*
AcknowledgementsWe are indebted to all participating research nurses, nurse anaesthetists, surgeons, other physicians and our patients. Without them the PROVHILO trial would never have been successful. We also thank Brigitte Leva and Sandrine Damster from the Research Team at the European Society of Anaesthesiology for their help and Annelou van der Veen for performing the on-site monitoring. We are particularly grateful to Prof. Daniel I. Sessler for revising the manuscript
List of supporting investigatorsAnn De Bruyne (Ghent University Hospital, Belgium), Patricia Ongena (ZNA Middelheim, Antwerpen, Belgium), Jörg-Uwe Bleyl, Moritz Koch, Michael Müller, Thomas Rössel, Hans-Detlef Saeger, Jürgen Weitz (University Hospital Dresden, Germany), Renate Babian, Anna Malina Rathmann (Heinrich-Heine-University Düsseldorf, Germany), Julia Pochert, Mandy Dathe (University of Leipzig, Germany), Fernando Chiaravalloti, Daniela Madia, Ivana Pezzoli, Andrea Caruso, Maria Francesca Bianco, Francesco Picicco (University “Magna Graecia” of Catanzaro, Italy), Lucia Mirabella, Michela Rauseo, Romina Anguilano (University of Foggia, Italy), Cesira Palmeri, Maria Teresa Strano, Antonino Federico (Università degli Studi di Palermo, Italy), Livia Pompei, Stefania Buttera (Università degli Studi di Udine, Italy), Kirsty Everingham, Ruth Han, Russell Hewson, Marta Januszewska, Otto Mohr, Rupert Pearse, Ashok Raj (Barts Health NHS Trust, London, U.K.), Jun Oto, Robert M. Kacmarek (Massachusetts General Hospital, Boston, U.S.A.), Toby N. Weingarten (Mayo Clinic, Rochester, Minnesota, U.S.A.)
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FundingThe European Society of Anaesthesiology (ESA) financially supported and endorsed the trial. The Academic Medical Center (AMC), Amsterdam, The Netherlands sponsored the trial. Neither the ESA nor the AMC had influence on trial design of the trial, conduct of the trial, data analysis, or reporting
Analysis treatment group (high peep) on the postoperative pulmonary complications, controlling for centerWe analysed the net effect of the treatment group (high peep) on the postoperative pulmonary complications, controlling for center. Therefore we explored the interaction (effect modification) and confounding. We first focussed on the crude (uncorrected) effect of the treatment group (independent variable) on postoperative pulmonary complications (dependent variable): Odds Ratio 1.04 (95% CI 0.80 - 1.37), p 0.76. Then the variable ‘center’ was added as an interaction term. If the interaction terms appeared to be significant (p<0.05), this would indicate that the relation between the treatment group and pulmonary complications could be different for various levels of the covariate (the centers). This would indicate the need for separate models to explore the levels of the covariate. A significant interaction was not found, so the model was examined for confounding: Odds Ratio 1.05 (95% CI 0.78 - 1.42). This concludes that there is no indication that heterogeneity between participating centers is of any significant influence. In conclusion ‘center’ as covariate is not an interaction term or a confounding term on the treatment effect: postoperative pulmonary complications
Figure S1. Kaplan-Meier curve for postoperative pulmonary complications: all patientsThe probability of the composite primary endpoint of postoperative pulmonary complications by postoperative day five as presented by a Kaplan–Meier and the 95% confidence interval
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Figure S2. Kaplan-Meier curve for extrapulmonary complications The probability of the composite endpoint of extrapulmonary complications by postoperative day five between the higher PEEP group (straight line) and the lower PEEP group (dotted line) as presented by a Kaplan–Meier graph (P = 0.83, log–rank test)
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Table S1. Inclusion and exclusion criteria
Inclusion criteria
Planned open abdominal surgery
General anaesthesia
High or intermediate risk for postoperative pulmonary complications following abdominal surgery, according to the ARISCAT risk score1 (higher or equal than 26) (table S2)
Exclusion criteria
Age < 18 years
Body mass index > 40 kg/m2
Laparoscopic surgery
Previous lung surgery (any)
Persistent hemodynamic instability, intractable shock (considered hemodynamic unsuitable for the study by the patient’s managing physician)
History of previous severe chronic obstructive pulmonary disease (COPD); non–invasive ventilation, and/or oxygen therapy at home or repeated systemic corticosteroid therapy for acute exacerbations of COPD
Recent immunosuppressive medication (receiving chemotherapy or radiation therapy within last 2 months)
Severe cardiac disease (New York Heart Association class III or IV, or acute coronary syndrome, or persistent ventricular tachyarrhythmia’s)
Mechanical ventilation > than 30 minutes (e.g., in cases of general anaesthesia because of surgery) within last 30 days
Pregnancy (excluded by laboratory analysis)
Acute lung injury or acute respiratory distress syndrome expected to require prolonged postoperative mechanical ventilation
Neuromuscular disease (any)
Consented for another interventional study or refusal to participate in the study
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Table S2. ARISCAT risk score Independent predictors of risk for post-operative pulmonary complications identified in the logistic regression model
High or intermediate risk for postoperative pulmonary complications ≥ 26
CI: confidence interval; OR: odds ratio; SpO2: oxyhemoglobin saturation by pulse oximetry breathing air in supine position; g/dL: gram per decilitre†The simplified risk score was the sum of each logistic regression coefficient multiplied by 10, after rounding off its value
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Table S3. Mechanical ventilation protocol for higher and lower PEEP groups
Mechanical ventilation settings Value
Ventilator Mode Volume controlled; just before tracheal extubation pressure support was allowed
Tidal Volume 8 ml/kg of predicted body weight
Inspiration : Expiration time 1:2
Respiratory Rate goal adjusted to achieve FE’CO2 between 35–45 mmHg
Fractional Inspired Oxygen 0.40 or higher to reach target SpO2 ≥ 92%
Rescue strategy with higher PEEP group
Step 1 2 3 4 5 6 7 8
FIO2 0.5 0.5 0.5 0.5 0.6 0.7 0.8 0.8
PEEP 12 10 8 6 6 6 6 4 or lower
Rescue strategy with lower PEEP group
Step 1 2 3 4 5 6 7 8 9
FIO2 0.5 0.6 0.6 0.6 0.6 0.7 0.8 0.8 RM
PEEP 2 2 3 4 5 5 5 6 6
Recruitment manoeuvre in higher PEEP group
Set peak inspiratory pressure limit at 45 cmH2OKeep tidal volume at 8 ml/kg PBW, PEEP at 12 cmH2O and inspiration : expiration time unchangedSet RR to 6–8 breaths/min, or lowest RR that ventilator allows Increase tidal volume in steps of 4 ml/kg of PBW, continue until plateau pressure = 30–35 cmH2O, and hold mechanical ventilation settings for 3 breathsSet RR and tidal volume back to values preceding the recruitment maneuver, keep PEEP at 12 cmH2O
FE’CO2: end–tidal carbon dioxide partial pressure; mmHg: millimetre of mercury; SpO2: oxyhaemoglobin saturation measured by pulse oximeter; FIO2: fraction inspired oxygen; RM: recruitment manoeuvre; PBW: predicted body weight, calculated according to a predefined formula: 50 + 0.91 x (centimetres of height – 152.4) for males and 45.5 + 0.91 x (centimetres of height – 152.4) for females; PEEP: positive end-expiratory pressure; RR: Respiratory Rate
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Table S4. Definitions of pulmonary postoperative complications
Postoperative pulmonary complications
Hypoxemia
PaO2 < 60 mmHg or SpO2 < 90% in room air, but responding to supplemental oxygen (excluding hypoventilation)
Severe hypoxemia
Need for non–invasive or invasive mechanical ventilation or a PaO2 < 60 mmHg or SpO2 < 90% despite supplemental oxygen (excluding hypoventilation)
Bronchospasm
Defined as newly detected expiratory wheezing treated with bronchodilators
Suspected pulmonary infection
In case patient receives antibiotics and meets at least one of the following criteria: new or changed sputum, new or changed lung opacities on chest X–ray when clinically indicated, tympanic temperature > 38.3°C, WBC count > 12 x109/L
Pulmonary infiltrate
Chest X–ray demonstrating monolateral or bilateral infiltrate
Aspiration pneumonitis
Defined as respiratory failure after the inhalation of regurgitated gastric contents
Acute Respiratory Distress Syndrome
By the consensus criteria (only in case of non–invasive or invasive mechanical ventilation)2
Atelectasis
Suggested by lung opacification with shift of the mediastinum, hilum, or hemidiaphragm towards the affected area, and compensatory overinflation in the adjacent nonatelectatic lung
Pleural effusion
Chest X–ray demonstrating blunting of the costophrenic angle, loss of the sharp silhouette of the ipsilateral hemidiaphragm in upright position, evidence of displacement of adjacent anatomical structures, or (in supine position) a hazy opacity in one hemi–thorax with preserved vascular shadows
Pulmonary oedema caused by cardiac failure
Defined as clinical signs of congestion, including dyspnoea, oedema, rales and jugular venous distention, with the chest X–ray demonstrating increase in vascular markings and diffuse alveolar interstitial infiltrates
Pneumothorax
Defined as air in the pleural space with no vascular bed surrounding the visceral pleura
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Table S5. Definitions of extra-pulmonary postoperative complications
Extra-pulmonary postoperative complications
Systemic inflammatory response syndrome (SIRS)3
Presence of two or more of the following findings: body temperature < 360C or > 380C; heart rate > 90 beats per minute; respiratory rate > 20 breaths per minute or on blood gas PaCO2 < 32 mmHg (4.3 kPa); WBC count < 4 x109/L or >12 x109/L, or > 10% band forms
Sepsis
SIRS in response to a confirmed infectious process; infection can be suspected or proven (by culture, stain, or polymerase chain reaction (PCR)), or a clinical syndrome pathognomonic for infection. Specific evidence for infection includes WBCs in normally sterile fluid (such as urine or cerebrospinal fluid), evidence of a perforated viscus (free air on abdominal X–ray or CT scan, signs of acute peritonitis), abnormal chest X–ray consistent with pneumonia (with focal opacification), or petechiae, purpura, or purpura fulminans
Severe sepsis
Sepsis with organ dysfunction, hypoperfusion, or hypotension
Septic shock
Sepsis with refractory arterial hypotension or hypoperfusion abnormalities in spite of adequate fluid resuscitation; signs of systemic hypoperfusion may be either end-organ dysfunction or serum lactate greater than 4 mmol/L. Other signs include oliguria and altered mental status. Patients are defined as having septic shock if they have sepsis plus hypotension after aggressive fluid resuscitation, typically upwards of 6 litres or 40 ml/kg of crystalloid
Extrapulmonary infection
Wound infection or any other infection
Coma
Glasgow Coma Score < 8 in the absence of therapeutic coma or sedation
Acute myocardial infarction4
Detection of rise and/or fall of cardiac markers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit, together with: symptoms of ischemia, ECG changes indicative of new ischemia, development of pathological Q-waves, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, or: sudden unexpected cardiac death, involving cardiac arrest with symptoms suggestive of cardiac ischemia (but death occurring before the appearance of cardiac markers in blood)
Acute renal failure (ARF)5
Renal failure documented as follows: Risk: increased creatinine x1.5 or glomerular filtration rate (GFR) decrease > 25% or urine output (UO) < 0.5 ml/kg/h x 6 h; Injury: increased creatinine x2 or GFR decrease > 50% or UO < 0.5 ml/kg/h x 12 hr; Failure: increase creatinine x3 or GFR decrease > 75% or UO < 0.3 ml/kg/h x 24 hr or anuria x 12 hrs; Loss: persistent ARF = complete loss of kidney function > 4 weeks
Serum bilirubin level > 34 µmol/L with elevation of the transaminase and lactic dehydrogenase levels above twice normal values
Gastro–intestinal failure7
Gastro–intestinal bleeding
Gastro–intestinal failure (GIF) score documented as follows: 0 = normal gastrointestinal function; 1 = enteral feeding with under 50% of calculated needs or no feeding 3 days after abdominal surgery; 2 = food intolerance (FI) or intra–abdominal hypertension (IAH); 3 = FI and IAH; and 4 = abdominal compartment syndrome (ACS)
Impaired wound healing
Interruption in the timely and predictable recovery of mechanical integrity in the injured tissue
Table S6. Specification recruitment manoeuvres in the higher PEEP group
Condition % (n/N) Reasons
All RM as indicated by the protocol 86 (378/442)
Neither RMs after intubation nor before extubation 1 (6/442)
Misunderstanding of the study protocol by the local investigator (n = 3), RM after intubation not performed because of hypotension, RM before extubation not performed because of massive bleeding (n = 1); reason not recorded (n = 2)
No RM before extubation, but RM after intubation performed 13 (58/442)
Forgotten (n = 3), logistic reasons (n = 2), misunderstanding of the study protocol by the local investigator (n = 17), reason not recorded (n = 36)
RM: recruitment manoeuvre
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Table S7a. Specification of rescue strategy for desaturation
Total subjects Maintained PEEP/FiO2
modificationShortPEEP/FiO2 modification
Lower PEEP 34 23 11
Higher PEEP 11 7 4
Table S7b. Highest step of rescue strategy for desaturation
Step n
Lower PEEP 1 5
N = 34 2 8
3 1
4 0
5 9
6 4
7 0
8 1
9 0
Not recorded 6
Higher PEEP 1 4
N = 11 2 2
3 1
4 1
5 1
6 0
7 0
8 0
Not recorded 2
The duration modification of FiO2 and/or PEEP was left to the discretion of to the attending anaesthesiologist.
In the lower PEEP group 11 out of 34 patients received short FiO2 and/or PEEP modifications, after which the ventilator settings were resumed according to the protocol:
- 5 patients received modification during less than 1 hour - 3 patients received modification during one hour - 3 patients received modification during two hours
In the higher PEEP group 3 out of 11 patients received short FiO2 and/or PEEP modifications: - 3 patients received modification during less than 1 hour - 1 patient received modification during one hour
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Table S8. Postoperative surgical complications*
Variable – % (n/N) Higher PEEPn=445
Lower PEEPn=449 p value
Bleeding surgical site 16 (71/444) 13 (58/58446) 0.21
Anastomosis bleeding 2 (8 /400) 1 (5/449) 0.29
Anastomosis leakage 0.7 (3/429) 0.4 (2/449) 0.62
Anastomosis necrosis 4 (18/445) 4 (20/449) 0.76
Fistulation 0.2 (1/445) 0.2 (1/449) 1.0
Other 2 (11/445) 1.7 (8/449) 0.47
*Reported surgical complications on postoperative day one to day of discharge
Table S10a. Per protocol analysis of patients receiving complete higher PEEP strategy
Higher PEEPN=445
Lower PEEPN=449 Total
Received complete higher PEEP strategy 368 2* 370
All other patients 77$ 447 524
Two patients in the lower PEEP group were ventilated with the complete higher PEEP strategy
$Protocol deviation from higher PEEP strategy was defined as ventilation with PEEP <10 cmH2O during 2 or more subsequent time points and/or missing 1 or more recruitment manoeuvres
Table S10b. Per protocol analysis of postoperative pulmonary complications
Data is presented as means ± (sd), median [IQR] or proportion % (n/N); n: number of patients; N: total patients and relative risk with 95% Confidence Intervals; PPCs: postoperative pulmonary complications; PPC = 0: no development of PPCs; PPC = 1: development of 1 or more PPCs.Variables tested in the model were selected if the p value was <0.20 and were clinically relevant parameters * actual values are OR 1.0002278 (1.00011586/1.000342) Odds Ratio for one change in unit (ml) minute ventilation **actual values are OR 1.0008824 (1.000546/1.0012656) Odds Ratio for one change in unit (ml) bloodloss
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CONSORT 2010 checklist of information to include when reporting a randomised trial
Section/Topic Item No Checklist item Reported on page
No
Title and abstract
1a Identification as a randomized trial in the title 235
1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 236
Introduction
Background and objectives
2a Scientific background and explanation of rationale 237
2b Specific objectives or hypotheses 237
Methods
Trial design3a Description of trial design (such as parallel, factorial) including
allocation ratio 238
3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons n.a.
Participants4a Eligibility criteria for participants 238, 239 &
Appendix p.268, 269
4b Settings and locations where the data were collected 238 & Appendix p.263, 264
Interventions 5The interventions for each group with sufficient details to allow replication, including how and when they were actually administered
239, 240 & Appendix p.270
Outcomes6a
Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed
240 & Appendix p. 271 – 273
6b Any changes to trial outcomes after the trial commenced, with reasons n.a.
Sample size7a How sample size was determined 240, 241
7b When applicable, explanation of any interim analyses and stopping guidelines 241
Randomisation
Sequencegeneration
8a Method used to generate the random allocation sequence 239
8b Type of randomisation; details of any restriction (such as blocking and block size) 239
Allocationconcealmentmechanism
9
Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned
239
Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions 239
210
Section/Topic Item No Checklist item Reported on page
No
Blinding11a
If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how
239
11b If relevant, description of the similarity of interventions n.a.
Statistical methods
12a Statistical methods used to compare groups for primary and secondary outcomes 241
12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 241
Results
Participant flow (a diagram is strongly recommended)
13aFor each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome
242, 256, 257
13b For each group, losses and exclusions after randomisation, together with reasons 242, 256, 257
Recruitment14a Dates defining the periods of recruitment and follow-up 242
14b Why the trial ended or was stopped n.a.
Baseline data 15 A table showing baseline demographic and clinical characteristics for each group 249 - 251
Numbers analysed 16
For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups
242, 249-258
Outcomes and estimation
17aFor each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval)
242, 254, 255
17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended n.a.
Ancillary analyses 18Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory
238, 242 – 246, 276 & Appendix p. 274 – 279
Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms)
242, 243, 254,255 & Appendix p.275, 276
Discussion
Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 245, 246
Generalizability 21 Generalizability (external validity, applicability) of the trial findings 244 – 246
Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 245, 246
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Other information
Registration 23 Registration number and name of trial registry 236, 238
Protocol 24 Where the full trial protocol can be accessed, if available 238
Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 236, 242
CONSORT Checklist for Reporting Randomized Controlled Trials in Journal and Conference Abstracts*
Item Description Reported on line number
Title Identification of the study as randomized p.235
Authors * Contact details for the corresponding author p.235
Trial design Description of the trial design (e.g. parallel, cluster, non-inferiority) p.236, line 9, 10
Methods
Participants Eligibility criteria for participants and the settings where the data were collected p. 236, line 9 - 13
Interventions Interventions intended for each group p. 236, line 11 - 12
Objective Specific objective or hypothesis p. 236, line 6 – 8
Outcome Clearly defined primary outcome for this report p. 236, line 14 - 15
Randomization How participants were allocated to interventions p. 236, line 13
Blinding (masking)Whether or not participants, care givers, and those assessing the outcomes were blinded to group assignment
p. 236, line 14
Results
Numbers randomized Number of participants randomized to each group p. 236, line 17 - 18
Recruitment Trial status n.a.
Numbers analysed Number of participants analysed in each group p. 236, line 21 - 22
Outcome For the primary outcome, a result for each group and the estimated effect size and its precision p. 236, line 21 - 22
Harms Important adverse events or side effects p. 236, line 23 - 24
Conclusions General interpretation of the results p. 236, line 1 – 2
Trial registration Registration number and name of trial register p. 236, line 15, 16
Funding Source of funding p. 236, line 26, 27
*This item is specific to conference abstracts
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References1. Canet J, Gallart L, Gomar C, et al. Prediction of Postoperative Pulmonary Complications in a Population-based Surgical
Cohort. Anesthesiology 2010; 113: 1338-502. Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European consensus conference on ARDS: definitions,
mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee. Intensive Care Med 1994; 20: 225-32
3. Bone RC. Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA 1992; 268: 3452-5
4. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007; 116: 2634-535. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure – definition, outcome measures, animal
models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204-12
6. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009; 145: 24-33
7. Reintam A, Parm P, Kitus R, Starkopf J, Kern H. Gastrointestinal failure score in critically ill patients: a prospective observational study. Crit Care 2008; 12: R90
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Chapter 9
Positive end-expiratory pressure during surgery - Authors’ reply
Hemmes SNT, Gama de Abreu M, Pelosi P, Schultz MJLancet 2014; 8; 384(9955):1670-1
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Positive end-expiratory pressure during surgery – Comments Hans-Joachim Priebe (Department of Anaesthesia, University Hospital Freiburg, Germany)
With great interest, I read the Article by PROVE Network Investigators (Aug 9, p 495)1 and the accompanying Comment.2 Some of the study limitations that might have obscured any treatment effect (e.g., protocol deviations, infrequent recruitment manoeuvres, and a high positive end-expiratory pressure [PEEP] level in the higher PEEP group) have been addressed in the accompanying Comment.2 Several additional factors might have negated any potential treatment effect.
39% of patients in both groups had received thoracic epidural analgesia. Compared with systemic analgesia, thoracic epidural analgesia can be expected to improve the postoperative pulmonary outcome in patients undergoing abdominal surgery.3 At the same time, the combination of thoracic epidural analgesia, general anesthesia, and mechanical ventilation frequently causes hypotension, which requires therapy.4 Any possible difference in pulmonary outcome between groups might have been obscured by the beneficial pulmonary effects of thoracic epidural analgesia. Similarly, the higher incidence of intraoperative hypotension and increased need for vasoactive drugs in the high compared with the low PEEP group might not have mainly been caused by the high PEEP per se but instead by the combination of high PEEP, thoracic epidural analgesia, and general anaesthesia. To compare the primary and secondary outcome variables between patients with and without thoracic epidural analgesia would be relevant. Combined abrupt withdrawal of 12 cmH2O PEEP and restoration of spontaneous respiration at the time of extubation will have acutely increased venous return and, in turn, right and left ventricular preload. This might have increased lung water in patients with left ventricular dysfunction with unpredictable subsequent adverse pulmonary sequelae.
All patients had received intermediate long acting muscle relaxants. Residual neuromuscular blockade must be expected at the end of surgery in up to 80% of cases.5 Residual neuromuscular blockade is associated with impaired postoperative lung function and postoperative pulmonary morbidity.5,6 Because the detrimental effect of residual neuromuscular blockade on postoperative pulmonary outcome might have obscured any potential treatment effects, we need to know whether neuromuscular function was quantitatively assessed before extubation. Extubation during an inspired oxygen fraction (FiO2) of 1.0 is associated with worse postextubation atelectasis and oxygenation compared with extubation at a lower FiO2.7 Use of a FiO2 of 1.0 at the time of extubation in all patients might partly explain the absence of difference in postoperative atelectasis.
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References1. The PROVE Network Investigators for the Clinical Trial Network of the European Society of Anaesthesiology. High
versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial. Lancet 2014; 384: 495–503
2. Futier E. Positive end-expiratory pressure in surgery: good or bad? Lancet 2014; 384: 472–743. Popping DM, Elia N, Marret E, Remy C, Tramèr MR. Protective effects of epidural analgesia on pulmonary complications
after abdominal and thoracic surgery. A metaanalysis. Arch Surg 2008; 143: 990–994. De Kock M, Laterre P-F, Andruetto P, et al. Ornipressin: an efficient alternative to counteract hypotension during
combined general/epidural anesthesia. Anesth Analg 2000; 90: 1301–075. Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology 2010; 112:
1013–226. Berg H, Viby-Mogensen J, Roed J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary
complications: A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand 1997; 41: 1095–103
7. Benoit Z, Wicky S, Fischer J-F, et al. The effect of increased FiO2 before tracheal extubation on postoperative atelectasis. Anesth Analg 2002; 95: 1777–81
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Positive end-expiratory pressure during surgery – Comments Farouk Mike Elkhatib, Mohamad Khatib (Department of Anesthesiology, School of Medicine (FME), American University of Beirut, Beirut, Lebanon)
We read with interest the PROVHILO study1 comparing high with low positive end-expiratory pressure (PEEP) during general anaesthesia for open abdominal surgery. The researchers concluded that high PEEP and recruitment manoeuvres during open abdominal surgery do not protect against postoperative pulmonary complications.1 We commend the investigators for providing such highly needed data; however, we believe that a major contributing factor that could have masked the potential benefit of high PEEP is the fact that peak inspiratory pressure was significantly higher in patients exposed to high PEEP than those exposed to low PEEP. The fact that high-peak airway and alveolar pressures per se are associated with ventilator-induced lung injury secondary to alveolar overdistention is well known.2
The PROVHILO study1 should have considered decreasing the tidal volume (VT) in the high-PEEP group to whatever level is needed to achieve in the high-PEEP group a peak airway pressure that is similar to that of the low-PEEP group. As such, one would expect higher PEEP with lower VT to maintain the same peak airway pressure that might result in improved lung compliance secondary to enhanced alveolar recruitment with high PEEP while preventing hyperinflation or overdistention in non-dependent lung units by the decrease in VT.3 Furthermore, reduction in peak airway pressure in the high PEEP group will lead to a decrease in mean airway pressure and potentially less haemodynamic impairment in the high-PEEP group.4 Perhaps only prevention of all forms of ventilator-induced lung injury (ie, cyclic opening and closing of alveoli and alveolar overdistention) can reduce or eliminate complications in mechanically ventilated patients.5
References1. The PROVE Network Investigators for the Clinical Trial Network of the European Society of Anaesthesiology. High
versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial. Lancet 2014; 384: 495–503
2. Futier E, Constantin JM, Paugam-Burtz C, et al, and the IMPROVE Study Group. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. NEJM 2013;369: 428–37
3. Severgnini P, Selmo G, Lanza C, et al. Protective mechanical ventilation during general anesthesia for open abdominal surgery improves postoperative pulmonary function. Anesthesiology 2013; 118: 1307–21
4. Luecke T, Pelosi P. Clinical review: Positive end-expiratory pressure and cardiac output. Crit Care 2005; 9: 607–215. Melo MF, Eikermann M. Protect the lungs during abdominal surgery: it may change the postoperative outcome.
Anesthesiology 2013; 118: 1254–57
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Authors’ reply Emmanuel Futier,1 Farouk Mike Elkathib and Mohamad Kathib, and Hans-Joachim Priebe’s comments about the results of PROVHILO2 raise relevant issues that deserve consideration.
Firstly, PROVHILO is the only trial of intraoperative ventilation that compared different levels of positive end-expiratory level (PEEP) in low tidal volume ventilation, which is now the standard of care.3,4 Notably, results from one metaanalysis5 show that the benefit from lung-protective ventilation is better explained by the use of low tidal volumes than the use of high levels of PEEP. A simultaneous reduction in tidal volume size in the high PEEP group in PROVHILO, to limit peak airway pressures, would not only have contradicted current practice but also have made identification of the individual role of high levels of PEEP impossible. Although we agree that high airway pressures could lead to increased ventilator-induced lung injury, mean peak inspiratory pressures were 23 cm H2O in the high PEEP group, i.e. below the commonly accepted safety limit.
Differently from the claim by Futier,1 several trials show that an intraoperative PEEP level of 10 cmH2O or more is necessary to avoid lung volume loss, and is not associated with overdistension.6 In PROVHILO, dynamic compliance improved in the high PEEP group, suggesting effective lung recruitment without relevant overdistension. Furthermore, periodic recruitment manoeuvres7 are not considered essential to keep lungs open when appropriate levels of PEEP are used, even with use of high inspiratory oxygen concentrations.8 Also, the suggestion that high oxygen concentrations during extubation could induce postoperative atelectasis has recently been challenged.9 We also do not ascribe pulmonary complications to abrupt changes in intrathoracic pressures during extubation, as a stepwise and gentle approach was used in which the mean airway pressure was reduced first, before resuming spontaneous breathing—a strategy that lasted several minutes, as usual in clinical practice.
Several additional analyses were requested. In an analysis of patients who received high levels of PEEP and received recruitment manoeuvres after intubation, after disconnection of the ventilator and before extubation (363 patients), versus patients who received low levels of PEEP without recruitment manoeuvres at any time (441 patients), the occurrence of postoperative pulmonary complications was not different (35% vs 36%; p=0.80). Likewise, in the 445 patients without thoracic epidural anaesthesia, the incidence of postoperative pulmonary complications did not differ between PEEP groups (48 vs 42%; p=0.26). Finally, in 265 patients who were monitored for and showed no residual neuromuscular blockade, the occurrence of postoperative pulmonary complications was independent of the level of PEEP (50% vs 45%; p=0.13).
Differently from a recent retrospective, one-centre study,4 results from PROVHILO1 convincingly showed that in non-obese patients undergoing open abdominal surgery, a low tidal volume strategy combined with low levels of PEEP is not associated with any disadvantage in terms of clinical outcome. In fact, use of high levels of PEEP was associated with impaired hemodynamics, mandating the increased use of fluids and vasoactive drugs in the intraoperative period.
PROVHILO clearly answers Futier’s question “positive end-expiratory pressure in surgery: good or bad?” in the patient group being studied. When a low tidal volume strategy is used, a low
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PEEP level without recruitment manoeuvres does not increase the incidence of postoperative pulmonary complications and is associated with less haemodynamic impairment compared with high PEEP with recruitment manoeuvres. These results need to be confirmed in morbidly obese patients and in patients undergoing thoracic surgery. We hope that beliefs and myths regarding PEEP during general anaesthesia will soon give place to the evidence of large randomised controlled trials.
References1. Futier E, Constantin JM, Paugam-Burtz C, et al, and the IMPROVE Study Group. A trial of intraoperative low-tidal-volume
ventilation in abdominal surgery. NEJM 2013; 369: 428–372. The PROVE Network Investigators for the Clinical Trial Network of the European Society of Anaesthesiology. High
versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial. Lancet 2014; 384: 495–503
3. Jaber S, Coisel Y, Chanques G, et al. A multicentre observational study of intra-operative ventilatory management during general anaesthesia: tidal volumes and relation to body weight. Anaesthesia 2012; 67: 999–1008
4. Levin MA, McCormick PJ, Lin HM, Hosseinian L, Fischer GW. Low intraoperative tidal volume ventilation with minimal PEEP is associated with increased mortality. Br J Anaesth 2014; 113: 97–108
5. Serpa Neto A, Hemmes SN, Barbas CS, Gama de Abreu M, Pelosi P, Schultz MJ. Intraoperative ventilator settings and postoperative acute respiratory distress syndrome: an individual data metaanalysis of 3 659 patients. ATS 2014 International Conference; San Diego; May 16–21, 2014
6. Satoh D, Kurosawa S, Kirino W, et al. Impact of changes of positive end-expiratory pressure on functional residual capacity at low tidal volume ventilation during general anesthesia. J Anesth 2012; 26: 664–69
7. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. NEJM 2013; 369: 2126–368. Neumann P, Rothen HU, Berglund JE, Valtysson J, Magnusson A, Hedenstierna G. Positive end-expiratory pressure
prevents atelectasis during general anaesthesia even in the presence of a high inspired oxygen concentration. Acta Anaesthesiol Scand 1999; 43: 295–301
9. Edmark L, Auner U, Lindback J, Enlund M, Hedenstierna G. Post-operative atelectasis—a randomised trial investigating a ventilatory strategy and low oxygen fraction during recovery. Acta Anaesthesiol Scand 2014; 58: 681–88
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Chapter 10
Incidence of mortality and morbidity related to postoperative lung injury in patients who have undergone abdominal or thoracic surgery: a systematic review and metaanalysis
Serpa Neto A, Hemmes SNT, Barbas CS, Beiderlinden M, Fernandez-Bustamante A, Futier E, Hollmann MW, Jaber S, Kozian A, Licker M, Lin WQ, Moine P, Scavonetto F, Schilling T, Selmo G, Severgnini P, Sprung J, Treschan T, Unzueta C, Weingarten TN, Wolthuis EK, Wrigge H, Gama de Abreu M, Pelosi P, Schultz MJ for the PROVE Network investigators. Lancet Respiratory Medicine 2014; 2(12):1007-15
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Abstract
Background. Lung injury is one of the most serious complications following surgery. Development of postoperative lung injury and its effect on outcome could depend on ventilator settings during the surgical procedure. We performed a systematic review and metaanalysis to estimate the incidence and determined the crude and attributable morbidity and in-hospital mortality of postoperative lung injury in published investigations of intra-operative ventilation for abdominal or thoracic surgery.
Methods. Observational studies and randomized controlled trials were identified by a systematic search of MEDLINE, CINAHL, Web of Science, and CENTRAL and screened for inclusion into a metaanalysis. Key inclusion criteria were: adults; ventilation for general anesthesia for abdominal or thoracic surgery; use of protective versus conventional ventilation. Individual patient data were obtained from the corresponding authors. Attributable mortality was calculated subtracting the in-hospital mortality rate of patients who did not develop postoperative lung injury from those who developed postoperative lung injury in predefined patient groups.
Findings. Data from 12 investigations were included, comprising 3,365 patients. The total incidence of postoperative lung injury in abdominal and thoracic surgery patients was similar (3.4 vs. 4.3%; p = 0.198). Patients who developed postoperative lung injury were older, had higher ASA scores, higher prevalence of sepsis or pneumonia, more frequently had received blood transfusions during surgery, and ventilation with higher tidal volumes and/or lower positive end-expiratory pressure levels. The occurrence of postoperative lung injury was associated with longer stay in intensive care unit and hospital (8 ± 13 vs. 1 ± 4 days; p < 0.001, and 21 ± 18 vs. 15 ± 14 days; p < 0.001, respectively), and increased in-hospital mortality (20.3 vs. 1.4%; p < 0.001). Overall attributable mortality of postoperative lung injury was 19% [95% confidence interval 18–19%), and differed between abdominal and thoracic surgery patients (12% vs. 27%, respectively; p < 0.001) but it was independent from intra-operative ventilator settings.
Interpretation. Development of postoperative lung injury was associated with increased in–hospital mortality and by a longer ICU and hospital lengths of stay. Attributable mortality of postoperative lung injury is higher in thoracic than in abdominal surgery patients. Protective mechanical ventilation reduces the incidence of postoperative lung injury but seems to have no effect on attributable mortality of this condition.
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Introduction
More than 230 million major surgical procedures are undertaken worldwide each year.1 Postoperative complications after major surgery increase resource use and are an important cause of death.1 Especially postoperative pulmonary complications, including postoperative lung injury, are suggested to have a strong impact on morbidity and mortality of patients who need major surgery.2-4 There is growing evidence that so–called intra–operative lung–protective mechanical ventilation with low tidal volumes and with or without high levels of positive end–expiratory pressure (PEEP) prevents postoperative lung injury compared to conventional ventilation with the use of high tidal volume levels and low levels of PEEP.2-4 Recently, in a report of a large retrospective study that showed use of low tidal volumes during general anesthesia for surgery to be associated with increased mortality, it was suggested that excess mortality could have been caused by the use of too low levels of PEEP.5
The exact impact of postoperative lung injury on morbidity and mortality is uncertain, and the outcome of postoperative lung injury could be different in patients who had abdominal surgery from those who underwent thoracic surgery. In addition, the impact of lung–protective ventilation on outcome of patients developing postoperative lung injury needs to be better defined.2-4 Indeed, it seems possible that outcome of lung injury is different according to the strategy of intraoperative ventilation.
A better understanding of the incidence, morbidity and mortality of postoperative lung injury may help design future trials, and possibly improves the approach to this condition, therefore, we performed an individual patient data metaanalysis of studies and trials of intra–operative ventilation for abdominal and thoracic surgery, which offered the possibility to quantify crude and attributable mortality of postoperative lung injury and its relationship with the strategy of ventilation used during surgery. We compared patients after abdominal surgery with patients after thoracic surgery, and related the outcome to intra–operative ventilator settings. We hypothesized that crude and attributable mortality are different between abdominal and thoracic surgery. In addition we hypothesized outcome of postoperative lung injury to be dependent on intraoperative ventilation settings.
Methods
The full statistical analysis plan of this collaborative metaanalysis has been published before.6
Search strategyTwo authors performed a computerized blinded search of MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) up to April 2014. The sensitive search strategy combined the following Medical Subject Headings and Keywords ([protective ventilation OR lower tidal volume OR low tidal volume OR positive end–expiratory pressure OR positive end–expiratory pressure OR PEEP]). All reviewed articles and cross–referenced studies from retrieved articles were screened for pertinent information. We ran a computerized search of proceedings of annual meetings
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from critical care and anaesthesiology societies to identify relevant studies published in abstract form only.
Selection of studiesObservational studies and randomized controlled trials comparing different tidal volume and PEEP settings during intraoperative ventilation for surgical general anesthesia identified by the search criteria and reporting outcomes of interest were screened for inclusion with no restrictions on language. Key inclusion criteria were: adults (i.e., age > 18 years); patients receiving ventilation for general anesthesia for abdominal or thoracic surgery; use of protective versus conventional ventilation. Studies or trials were excluded from this metaanalysis if they: included patients with pre–existing lung injury; or reported on patients receiving ventilation in a non–surgical setting (i.e., continued ventilation in the intensive care unit). The Jadad score was used to assess the quality of the randomized controlled trials and the GRACE checklist to observational studies.
Collection of individual patient dataCorresponding authors of the identified eligible published studies were contacted via email with a letter detailing background and objectives of this metaanalysis, and a datasheet for input of individual patient data. The filled out data templates were sent back to the principal investigator and further communication was by email. Corresponding authors were also contacted on unpublished data, if present to enlarge the clinical data pool. The same two investigators who performed the electronic database search handled the individual patient data provided by the corresponding authors. Data was accepted in any kind of electronic format (SPSS, STATA, Word document, Excel document, and Access document) and only the coordinators of the collaboration have direct access to the data. Both authors performed data validation, checking the received data set for data entry mistakes and inconsistency. Differences were discussed and settled in consensus.
DefinitionsFor postoperative lung injury we used the definitions for acute lung injury and ARDS from the American–European Consensus criteria group (PaO2 / FiO2 < 300),7 since all studies were conducted before the publication of the Berlin definition; follow–up was defined as the time between the day of the surgery and hospital discharge, or in–hospital death. The number of ICU and hospital–free days and alive by day 28 was defined as the mean number of days on which patients were outside the ICU or hospital and alive from day 1 to day 28. Protective ventilation was defined as ventilation using low tidal volume (defined as a tidal volume ≤ 8 ml/kg predicted body weight [PBW]) with or without high levels of PEEP (defined as PEEP ≥ 5 cmH2O) and with or without recruitment manoeuvres. Conventional ventilation was defined as ventilation using high tidal volume (> 8 ml/kg PBW) with low levels of PEEP (< 5 cmH2O) and without recruitment manoeuvres. The definition of protective and conventional ventilation was made based on several reports in the literature and according to the previously published protocol.2-4
Statistical analysisAttributable morbidity was calculated by subtracting the in–hospital mortality rate of patients without postoperative lung injury from the in–hospital mortality of patients with postoperative lung injury. The incidence rate was calculated as number of cases person-years = ([number of
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cases / person-day] x [365 person-day / 1 person-year]). A random-effect model was used to pool the overall data.
Survival curves were constructed using the Kaplan–Meier methods and compared using the log–rank test. Time–to–event was defined as time from the day of surgery to the event. We used a Cox proportional–hazards regression model to examine simultaneously effects of multiple covariates on outcome, censoring a patient’s data at the time of death, hospital discharge, or after 30 days. The initial model included age, sex, body mass index, ASA (American Society of Anesthesiology score), smoking, and predisposing conditions [defined as shock, pneumonia, blood transfusion and/or sepsis]). Variables with p < 0.2 in the univariate analysis are included in the multivariate regression. The final model was developed by dropping each variable in turn from the model and conducting a likelihood-ratio test to compare the full and the nested models (stepwise backward approach). We used a significance level of 0.05 as the cut-off to exclude a variable from the model. In all models, the categorical variables were tested for trend with the absence of postoperative lung injury as reference and the proportional–hazards assumption was assessed. A test for interaction between pairs of variables in the final model was performed. Interaction between biological plausible variable was assessed. The effect of each variable in these models was assessed with the use of the Wald test and described by the HR with 95% CI.
Subgroup analyses were performed to examine the effects of intra–operative ventilation (conventional vs. lung–protective ventilation), age (< 65 vs. ≥ 65 years), surgery (abdominal vs. thoracic) and severity of illness (ASA score < 3 or ≥ 3).
All analyses were conducted with SPSS v.20 (IBM Corporation, New York, USA) and R v.2.12.0 (R Foundation for Statistical Computing, Vienna, Austria). For all analyses two–sided p values < 0.05 were considered significant.
Results
Search results and collection of individual patient dataThe search identified three observational studies and 21 randomized controlled trials comparing different tidal volume and/or PEEP settings in intra–operative ventilation during general anaesthesia for major surgery.8-31 We were not able to collect data from five randomized controlled trials due to the following reasons: the corresponding author could not provide data of interest or had no longer access to the complete database (n = 3);20-22 or the corresponding author could not be contacted (n = 2).23,24 Seven papers were excluded because assessed patients under cardiac (n = 6)25-30 or orthopaedic surgery (n = 1).31 The total enrolment based on the studies and trials for which individual patient data could be collected was 3,365 patients (table 1, Appendix figure 1, Appendix tables 2, Appendix table 3, and Appendix table 4).
Characteristics of patients who did or did not developed postoperative lung injuryBaseline characteristics and predisposing conditions differed between patients who did and those who did not develop postoperative lung injury (table 2). Patients who developed postoperative
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IPD metaanalysis postoperative lung injury
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lung injury were older, presented higher ASA score, higher prevalence of sepsis or pneumonia, more frequently had received blood transfusion, and were ventilated with higher tidal volumes and/or lower PEEP levels (table 2). Baseline characteristics stratified according to the type of surgery are shown in the Appendix table 5 and Appendix table 6. Ventilatory parameters and duration of ventilation in patients ventilated with a protective or conventional strategy of ventilation are shown in Appendix table 7.
Incidence and timing of postoperative lung injuryThe incidence of postoperative lung injury in the whole cohort was 3.9% (crude incidence 0.99 cases per person-year). The individual and pooled postoperative lung injury incidence rates are shown in Appendix figure 8. The incidence of postoperative lung injury was higher in patients older than 65 years (4.7 vs. 2.8%; p = 0.008), and in those ventilated with conventional ventilation (6.7 vs. 2.0%; p < 0.001), while it was similar after abdominal or thoracic surgery (3.4 vs. 4.3%; p
PLI: postoperative lung injury; BMI: body mass index; PBW: predicted body weight; BPM: breaths per minute; FiO2: inspired fraction of oxygen; ICU: intensive care unit; LOS: length of stay; PEEP: positive-end expiratory pressure*: in the middle of the surgery
230
= 0.198) (Table 3). The results stratified according to type of surgery are shown in the Appendix table 9 and Appendix table 10. The development of postoperative lung injury occurred within the first three days after surgery (mean of 2.9 ± 2.2 days; median and interquartile range of 2.0 [2.0 – 3.0] days); in 22% of cases postoperative lung injury developed after the first postoperative day (table 3 and figure 1).
Outcomes of postoperative lung injuryOutcome data for the study cohort are shown in table 3 and 4. Development of postoperative lung injury was associated with an increased in–hospital mortality (20.3 vs. 1.4% in patients with or without postoperative lung injury, respectively; p < 0.001) and by a longer ICU (8 ± 13 vs. 1 ± 4 days; p < 0.001) and hospital (21 ± 18 vs. 15 ± 14 days; p < 0.001) lengths of stay. The number of ICU–free days at day 28 and hospital–free days at day 28 were lower in patients who developed postoperative lung injury (21 ± 8 vs. 27 ± 2 days; p < 0.001; and 10 ± 7 vs. 15 ± 7 days; p < 0.001). When adjusted for age, severity of illness using ASA score, smoking, and predisposing conditions (sepsis, pneumonia, transfusion and/or shock), development of postoperative lung injury markedly increased the risk of in–hospital mortality (adjusted hazard ratio [HR], 9.58; 95% CI, 5.32 – 17.34) (figure 2 & 3, table 4 and Appendix figure 11). Patients who developed postoperative lung injury had a lower chance per day for ICU discharge, as represented by the adjusted HR of 0.45 (95% CI, 0.33 – 0.66) (table 4). The estimate of attributable mortality due to postoperative lung injury was 19% (95% CI, 18.0 – 19.1%).
In the group of patients who did develop postoperative lung injury, total duration of mechanical ventilation, ICU and hospital length of stay was similar between survivors and non–survivors
Figure 1. Timing of postoperative lung injury development during hospital stayThe day of surgery is marked as Day 0
IPD metaanalysis postoperative lung injury
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(Appendix table 12). The mean time to death was 35.2 ± 63.4 days and the median was 18.0 (10.0 – 31.0) days. Patients ventilated with conventional strategy during surgery died earlier than those ventilated with protective strategy (17.8 ± 13.1 vs. 51.2 ± 84.3 days; p = 0.027).
Outcomes of postoperative lung injury in predefined subgroupsThe attributable mortality of postoperative lung injury was lower in patients undergoing abdominal surgery (12.2% [95% CI, 12.0 – 12.6%]) compared to those undergoing thoracic surgery (26.5% [95% CI, 26.2 – 27.0%]) (p < 0.001). Development of postoperative lung injury was associated with a longer ICU and hospital lengths of stay, which was similar in abdominal and thoracic surgery patients (Appendix table 5 and Appendix table 6). When adjusted for age, severity of illness using ASA score, smoking, and predisposing conditions (sepsis, pneumonia, transfusion and/or shock), development of postoperative lung injury was lower in those receiving protective ventilation during surgery (adjusted HR, 0.31; 95% CI, 0.19 – 0.45). However, in–hospital mortality was independent of the ventilation strategy used in the operation room (adjusted HR, 0.71; 95% CI, 0.41 – 1.22). Attributable mortality of postoperative lung injury was similar in patients under protective ventilation (18.5% [95% CI, 17.8 – 19.2%]) compared to those under conventional ventilation (19.3% [95% CI, 19.0 – 19.7%]) (p = 0.359). Notably, patients who received conventional ventilation and developed postoperative lung injury died earlier compared to patients who received lung–protective ventilation and developed postoperative lung injury (18 ± 16 vs. 35 ± 53 days; p = 0.018). Characteristics of patients with postoperative lung injury stratified according to the type of ventilation used during surgery are shown in Appendix table
Figure 2. Kaplan–Meier estimates of the probability of overall survivalData for the Kaplan–Meier estimates of the probability of overall survival in patients without postoperative lung injury (black solid line), and patients with postoperative lung injury (black dotted line). Data were censored at 30 days after surgery
232
Tabl
e 3.
Inci
denc
e of
pos
tope
rativ
e lu
ng in
jury
and
its
char
acte
ristic
s in
all
grou
ps o
f pati
ents
*
Num
ber o
f Pati
ents
ICU
LO
S (d
ays)
Mor
talit
yO
nset
of P
LI
No
PLI
PLI
Inci
denc
e**N
o PL
IPL
Ip
valu
eN
o PL
IPL
Ip
valu
e
All p
atien
ts31
50 (9
6.1)
123
(3.9
)0.
991.
1 ±
3.7
8.0
± 12
.4<
0.00
145
(1.4
)25
(20.
3)<
0.00
12.
9 ±
2.2
Conv
entio
nal
venti
latio
n10
41 (9
3.3)
75 (6
.7)
1.71
1.0
± 3.
09.
2 ±
10.2
< 0.
001
17 (1
.4)
17 (2
0.7)
< 0.
001
2.5
± 1.
5
Prot
ectiv
e ve
ntila
tion
1762
(98.
0)37
(2.0
)0.
461.
3 ±
4.3
6.1
± 16
.2<
0.00
128
(1.5
)8
(20.
0)<
0.00
13.
9 ±
3.3
Age
<
65 y
ears
≥
65 y
ears
1504
(9.2
)13
90 (9
5.3)
44 (2
.8)
68 (4
.7)
0.76
1.02
0.8
± 2.
61.
5 ±
4.7
5.0
± 6.
010
.5 ±
15.
4<
0.00
1<
0.00
18
(0.5
)37
(2.5
)6
(12.
8)19
(25.
3)<
0.00
1<
0.00
12.
5 ±
1.2
3.2
± 2.
6
ASA
scor
e
< 3
≥
313
91 (9
6.6)
1106
(95.
3)49
(3.4
)55
(4.7
)0.
811.
141.
0 ±
4.0
1.8
± 4.
44.
2 ±
5.3
9.0
± 14
.40.
001
0.01
710
(0.7
)25
(2.3
)9
(17.
0)16
(29.
1)<
0.00
1<
0.00
12.
5 ±
1.2
3.4
± 2.
9
Surg
ery
Ab
dom
inal
Th
orac
ic17
98 (9
6.6)
1285
(95.
7)64
(3.4
)58
(4.3
)0.
791.
321.
0 ±
4.1
1.5
± 0.
99.
0 ±
14.5
5.9
± 2.
1<
0.00
1<
0.00
132
(1.8
)13
(1.0
)9
(14.
1)16
(27.
6)<
0.00
1<
0.00
12.
3 ±
0.9
3.4
± 2.
7
PLI:
post
oper
ative
lung
inju
ry; I
CU: i
nten
sive
care
uni
t; LO
S: le
ngth
of s
tay;
Ons
et o
f PLI
is e
xpre
ssed
in d
ays
* In
som
e ca
ses t
he n
umbe
r of p
atien
ts a
re n
ot a
ddin
g up
due
to m
issin
g va
lues
** E
xpre
ssed
as c
ases
per
per
son-
year
IPD metaanalysis postoperative lung injury
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13. There was no interaction between mortality and the design of the study (RCT versus No-RCT) in the overall cohort (p for interaction = 0.11), abdominal surgery (p for interaction = 0.23), or thoracic surgery (p for interaction = 0.78) (Appendix figure 14).
Based on the excluded studies where the data is available,21,23,24 the crude incidence of PLI was 6.6%, similar to that found in our study (p = 0.116). Also, protective ventilation was associated with lower incidence of PLI compared to conventional ventilation (5.3% vs. 13.1%; p = 0.031), similar to the findings of the present study. There was no interaction between mortality and PLI incidence and the excluded analysis (Appendix figure 15).
Discussion
This individual patient data metaanalysis shows that development of postoperative lung injury is associated with high attributable mortality. In addition, development of postoperative lung injury is associated with an important increase in resource use as reflected in longer ICU and hospital length of stay. The incidence of postoperative lung injury is similar in patients undergoing abdominal or thoracic surgery. However, the attributable mortality of this condition is higher in those submitted to thoracic procedures. Intraoperative protective ventilation is associated with lower incidence of postoperative lung injury compared to conventional ventilation in abdominal or thoracic surgery. However, if postoperative lung injury develops, intraoperative protective strategy of ventilation is not associated with reduced attributable mortality, at least suggesting that the benefits of this strategy of ventilation is mainly due the reduction in the incidence of postoperative lung injury.
Table 4. Outcome of patients with postoperative lung injury
Variable HR of Mortality (95% CI)
HR of ICU Discharge (95% CI)
All patients 9.58 (5.32 – 17.34) 0.45 (0.33 – 0.66)
HR: hazard ratio; ICU: intensive care unit; CI: confidence interval
234
Our analysis presents several strengths. First, we performed an individual patient data metaanalysis including a larger number of patients with a higher number of variables and well–documented risk factors compared to previous studies.1-4 Second, the primary and secondary outcomes were clearly defined in the majority of the investigations and the definition of postoperative lung injury was done a priori. Third, we included the two most recent largest and well–performed randomized controlled trials in the field.18,19 Fourth, we analysed patients undergoing abdominal and thoracic surgery and they are at high risk for development of postoperative lung injury.1 Finally, individual patient data metaanalysis including a higher number of randomized controlled trials have some advantages compared to large observational studies.
Since the number of major surgical procedures undertaken worldwide each year is high, the finding that postoperative lung injury is associated with such a bad outcome is important. Identification of mechanisms contributing to the development of this complication and finding of preventive measures is highly needed. The use of lower tidal volumes during intraoperative ventilation appears to be a clinically relevant and modifiable strategy.2,18 At the same time, ventilation strategies that use high PEEP levels are associated with potentially dangerous side–effects, as reported in the last randomized controlled trial comparing high with low PEEP levels in patients under intraoperative ventilation with low tidal volume.19
The results of this metaanalysis are, at least in part in line with results from previous investigations. Studies suggest that in patients undergoing high risk elective surgery,2 the reported incidence of postoperative lung injury was 3%, similar to what the present metaanalysis found.
Figure 3. Kaplan–Meier estimates of the probability of overall survivalData for the Kaplan–Meier estimates of the probability of overall survival in: A) patients undergoing thoracic surgery without postoperative lung injury (black solid line), patients undergoing thoracic surgery with postoperative lung injury (black dotted line), patients undergoing abdominal surgery without postoperative lung injury (gray solid line), and patients undergoing abdominal surgery with postoperative lung injury (gray dotted line); and in B) patients undergoing protective ventilation without postoperative lung injury (black solid line), patients undergoing protective ventilation with postoperative lung injury (black dotted line), patients undergoing conventional ventilation without postoperative lung injury (gray solid line), and patients undergoing conventional ventilation with postoperative lung injury (gray dotted line). Data were censored at 30 days after surgery. Abd: abdominal; Tho: thoracic; LI: lung injury; Pro: protective; Conv: conventional
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That same investigation showed a similar increased length of hospital stay in patients who developed postoperative lung injury, and an increased in–hospital mortality of as high as 17%. Furthermore, in that study 60–day and one–year survival of patients with postoperative lung injury was lower than that of patients who did not develop this complication. Studies in other patient groups show similar findings.12,22 It is important to emphasize that incidence and outcomes of postoperative lung injury might be different in different types of surgery3 and according to definitions used.
The findings of this metaanalysis add to our knowledge on the outcome of postoperative lung injury, and the potential measures to prevent this important complication after major surgery, mainly the use of protective strategies of mechanical ventilation during surgery. This is of particular importance for those who apply intraoperative ventilation, since most of the time they follow on patients’ outcomes only the first postoperative day. Indeed, the metaanalysis shows that many patients do develop lung injury after major surgery beyond the first postoperative day. Second, development of postoperative lung injury was dependent on the intraoperative ventilation strategy, and thus should be seen as a potentially preventable complication. Finally, the attributable mortality of postoperative lung injury after intraoperative ventilation using conventional settings is similar to those after lung–protective ventilation, meaning that the benefits of intraoperative protective ventilation is mainly due the reduction of the incidence of postoperative lung injury. This finding might simply reflects the heterogeneous factors that cause death in this population well beyond just postoperative lung injury.
The finding that patients who received conventional intra–operative ventilation and developed postoperative lung injury died earlier than those who developed this complication after protective intraoperative ventilation, even though attributable mortality at the end of follow up was the same, is intriguing. One possible explanation is that patients who did not receive intraoperative lung–protective ventilation could have been ventilated with injurious ventilation after surgery, and maybe even after development of lung injury. Unfortunately, it was impossible to collect data on ventilator settings after surgery, therefore our reasoning, although plausible, remains speculative.
The observed incidence and outcome of postoperative lung injury might not be easily appreciated during daily clinical work among physicians, surgeons, and anaesthesiologists involved in the perioperative management. In fact, this is a large cohort evaluating the development and impact of postoperative lung injury in patients undergoing elective abdominal and thoracic procedures. The finding that postoperative lung injury develops after the first postoperative day is important, suggesting we need a more precise timing for monitoring and clinical management.
Some limitations should also be discussed. First, our analyses were restricted to studies of intraoperative protective ventilation and data on postoperative ventilation are not available. Second, not all investigators could provide individual patient data, and, therefore, data from seven studies were not included. However, the results of a classical metaanalysis are in agreement with those found in the present analysis.4 Third, there was no information on choices of treatment after surgery, like postoperative ventilation, blood transfusion policies, fluid regimens, pain control, cardiac protection and others, and it could be anaesthetists that applied protective
236
ventilation also provided other lung protective strategies after surgery. Therefore, we cannot answer the question of how much the in–hospital mortality is influenced by the adequacy of treatment. Also, we do not know the reason of death in each patient. Fourth, since there is no gold standard for the diagnosis of postoperative lung injury, misclassification of patients with this complication might have underestimated as well as overestimated the observed attributable morbidity. Fifth, we were not able to collect information regarding history of previous abdominal or thoracic surgery, which can influence the outcome. Sixth, these results should be analysed within the context of the included studies and one limitation is that we pooled data from studies with heterogeneous research methodologies and with significant quantitative heterogeneity. Seventh, the number of studies included is moderate and therefore the model may lack power to detect association and are unable to ascertain multiple potential sources of confounding. Eight, we did not include previous pulmonary alterations as co-variate in the model however, only 4.9% of the population analysed presented chronic obstructive pulmonary disease (COPD) or other chronic pulmonary disease. Ninth, it should be noted that minimal invasive techniques for thoracic surgery are increasingly used, and these techniques usually last shorter and are associated with a shorter length of stay. Since the studies included in the present analysis did not include these techniques, we cannot assess the outcomes and effects of protective ventilation during minimal invasive procedures. However, a recent study suggests that protective ventilation strategies benefits patients undergoing minimally invasive esophagectomy as well.32 Finally, although the type of intraoperative ventilation appears to play an important role in development of acute lung injury, other factors during postoperative management may plausibly be contributory, especially for patients who developed lung injury days after surgery (or cessation of mechanical ventilation).
In conclusion, based on an individual patient data from seven studies of intraoperative protective ventilation, development of postoperative lung injury is associated with high attributable mortality. The attributable mortality of postoperative lung injury is higher in patients undergoing thoracic compared to abdominal surgery. Intraoperative protective ventilation is associated with lower incidence of postoperative lung injury, but seems not to affect in–hospital mortality.
Role of the funding sourceThe corresponding author had full access to all of the data and the final responsibility to submit for publication.
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Research in context
Systematic reviewWe searched MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) up to April 2014. The sensitive search strategy combined the following Medical Subject Headings and Keywords ([protective ventilation OR lower tidal volume OR low tidal volume OR positive end–expiratory pressure OR positive end expiratory pressure OR PEEP]). We restricted our analysis to studies in surgery. We assessed the quality of identified studies to ensure minimization of bias.
InterpretationDevelopment of postoperative lung injury is associated with high attributable mortality. The attributable mortality of postoperative lung injury is higher in patients undergoing thoracic compared to abdominal surgery. Intraoperative protective ventilation is associated with lower incidence of postoperative lung injury, but seems not to affect in–hospital mortality.
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surgery: a prospective randomized clinical trial. Intensive Care Med 2005; 31:1379-8728. Zupancich E, Paparella D, Turani F, et al. Mechanical ventilation affects inflammatory mediators in patients undergoing
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Supplementary Appendix to: ‘Incidence of mortality and morbidities of postoperative lung injury in abdominal and thoracic surgery patients: A systematic review and metaanalysis
Ary Serpa Neto MD MSc, Sabrine NT Hemmes MD, Carmen SV Barbas MD PhD, Martin Beiderlinden MD, Michelle Biehl MD, Ana Fernandez-Bustamante MD PhD, Emmanuel Futier MD PhD, Ognjen Gajic MD PhD, Samir Jaber MD PhD, Alf Kozian MD PhD, Marc Licker MD, Wen-Qian Lin MD, Stavros G Memtsoudis MD PhD, Dinis Reis Miranda MD, Pierre Moine MD, Domenico Paparella MD, Marco Ranieri MD PhD, Federica Scavonetto MD, Thomas Schilling MD PhD DEEA, Gabriele Selmo MD, Paolo Severgnini MD, Juraj Sprung MD PhD, Sugantha Sundar MD, Daniel Talmor MD PhD, Tanja Treschan MD, Gerardo Tusman MD PhD, Maria Carmen Unzueta MD, Toby N Weingarten MD, Esther K Wolthuis MD PhD, Hermann Wrigge MD PhD, Marcelo Gama de Abreu MD PhD, Paolo Pelosi MD, Marcus J Schultz MD PhD
eFigure 1. Literature search strategy
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eFigure 2. Individual and pooled incidence rate of postoperative lung injury
eFigure 3. In-hospital mortality in patients who developed or not postoperative lung injury in thoracic or abdominal surgery
242
eFigure 4. Interaction between mortality and design of the study
eFigure 5. Interaction between outcome and excluded studies
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eTable 1. Characteristics of included studies
Study, year Allocation Concealment Baseline Similarity Early
StoppingaLost to Follow-up
Intention-to-Treat Analysis
Wrigge, 2004 Sealed envelopes
Age: similarIllness severity: similar (ASA)
No 4.6% NS
Schilling, 2005 Random numbers Age: similar No No NS
Weingarten, 2010 ScheduleAge: similarIllness severity: similar (ASA)
No No NS
Treschan, 2012 Sealed envelopes
Age: similarIllness severity: similar (ASA)
No No Yes
Unzueta, 2012 Random tableAge: similarIllness severity: similar (ASA)
No No NS
Severgnini, 2013 Sealed envelopes
Age: similarIllness severity: similar (ASA)
No 1.7% NS
Futier, 2013 Computer-Generated
Age: similarIllness severity: similar (PORI)
No No Yes
Hemmes, 2014 Computer-Generated
Age: similarIllness severity: similar (ARISCAT)
No No Yes
NS: not specified; VT: tidal volume; STSMS: society of thoracic surgeons mortality score; PORI: preoperative risk indexa: Early termination for benefit or futility and the presence of an explicit a priori stopping rules
244
eTable 2. Jadad scale
StudiesWas the study described as randomized?
Was the study described as double blind?
Was there a description of withdrawals and dropouts?
The method of randomization was described in the paper, and that method was appropriate.
The method of blinding was described, and it was appropriate.
Fernandez, 2011 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes1Dreyer NA, Velentgas P, Westrich K, Dubois R. The GRACE checklist for rating the quality of observational studies of comparative effectiveness: a tale of hope and caution. J Manag Care Pharm 2014; 20: 301-8
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eTable 4. Demographics of patients undergoing thoracic surgery
PLI: postoperative lung injury; BMI: body mass index; PBW: predicted body weight; MPM: movements per minute; FiO2: inspired fraction of oxygen; ICU: intensive care unit; LOS: length of stay; *: in the end of the surgery
246
eTable 5. Demographics of patients undergoing abdominal surgery
PLI: postoperative lung injury; BMI: body mass index; PBW: predicted body weight; MPM: movements per minute; FiO2: inspired fraction of oxygen; ICU: intensive care unit; LOS: length of stay; *: in the end of the surgery
eTable 6. Ventilatory parameters and duration of ventilation
Parameters
Total Abdominal Thoracic
Protective(n = 1799)
Conventional(n = 1116) p value Protective
(n = 1155)Conventional(n = 707) p value Protective
BMI: body mass index; PBW: predicted body weight; MPM: movements per minute; FiO2: inspired fraction of oxygen; ICU: intensive care unit; LOS: length of stay; PEEP: positive-end expiratory pressure; *: in the middle of the surgery
IPD metaanalysis postoperative lung injury
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249
eTab
le 1
0. C
hara
cter
istic
s of
the
patie
nts
with
pos
tope
rativ
e lu
ng in
jury
und
er p
rote
ctive
or c
onve
ntion
al v
entil
ation
Varia
bles
Gen
eral
(n =
122
)
p-va
lue
Thor
acic
(n =
58)
p-va
lue
Abdo
min
al (n
= 6
4)
p-va
lue
Prot
ectiv
e (n
= 4
0)Co
nven
tiona
l (n
= 8
2)Pr
otec
tive
(n =
16)
Conv
entio
nal
(n =
42)
Prot
ectiv
e (n
= 2
4)Co
nven
tiona
l (n
= 4
0)
Age,
yea
rs64
.3 ±
14.
067
.4 ±
10.
20.
169
63.2
± 1
4.3
67.0
± 8
.40.
215
65.0
± 1
4.0
67.8
± 1
1.9
0.40
7
Gen
der,
mal
e28
(70.
0)50
(61.
0)0.
330
ASA
2.58
± 0
.72.
58 ±
0.6
0.94
72.
8 ±
0.5
2.7
± 0.
70.
523
2.4
± 0.
72.
4 ±
0.6
0.98
8
BMI,
kg/m
225
.7 ±
5.3
26.3
± 4
.50.
496
25.4
± 5
.525
.0 ±
3.9
0.75
226
.0 ±
5.3
27.9
± 4
.70.
144
Venti
lato
ry P
aram
eter
s*
Ti
dal v
olum
e, m
l/kg
PBW
PE
EP, c
mH 2
O
Resp
irato
ry ra
te, m
pm
FiO
2, %
7.4
± 1.
35.
7 ±
3.9
13.1
± 2
.440
.0 ±
4.4
10.3
± 1
.81.
5 ±
2.1
10.8
± 1
.441
.0 ±
4.1
< 0.
001
< 0.
001
< 0.
001
0.39
6
7.2
± 1.
92.
6 ±
1.5
13.5
± 1
.638
.5 ±
4.6
10.4
± 2
.11.
3 ±
1.6
10.9
± 1
.341
.4 ±
5.0
< 0.
001
0.00
8<
0.00
10.
068
7.5
± 0.
67.
8 ±
3.6
12.9
± 2
.855
.6 ±
22.
1
10.2
± 1
.31.
6 ±
2.5
10.7
± 1
.555
.8 ±
23.
1
< 0.
001
< 0.
001
< 0.
001
0.96
8
Oxy
gena
tion
Para
met
ers*
pH
a
PaO
2 / F
iO2
Pa
CO2
7.32
± 0
.11
258.
5 ±
103.
735
.5 ±
3.5
7.14
± 0
.16
317.
0 ±
181.
142
.1 ±
3.1
5
0.16
50.
367
0.20
4
--- --- ---
--- --- ---
--- --- ---
7.38
± 0
.01
247.
1 ±
104.
637
.1 ±
0.2
7.45
± 0
.03
345.
7 ±
257.
130
.5 ±
4.0
0.49
50.
318
0.08
1
Dura
tion
of v
entil
ation
, ho
urs
28.8
± 7
0.3
31.1
± 7
8.4
0.90
4---
---29
.9 ±
71.
640
.4 ±
89.
50.
626
ICU
LO
S, d
ays
6.1
± 16
.29.
2 ±
10.3
0.39
3---
---6.
3 ±
16.7
11.1
± 1
2.6
0.29
6
Hosp
ital L
OS,
day
s21
.2 ±
24.
120
.8 ±
14.
60.
905
20.1
± 5
.421
.0 ±
10.
20.
737
22.0
± 3
1.3
20.6
± 1
8.2
0.82
0
In-H
ospi
tal M
orta
lity,
%8
(20.
0)17
(20.
7)0.
925
4 (2
5.0)
12 (2
8.6)
0.78
64
(16.
7)5
(12.
5)0.
642
BMI:
body
mas
s ind
ex; P
BW: p
redi
cted
bod
y w
eigh
t; M
PM: m
ovem
ents
per
min
ute;
FiO
2: in
spire
d fr
actio
n of
oxy
gen;
ICU
: int
ensiv
e ca
re u
nit;
LOS:
leng
th o
f sta
y; P
EEP:
pos
itive
-end
ex
pira
tory
pre
ssur
e; *
: in
the
mid
dle
of th
e su
rger
y
Chapter 11
Positive end – expiratory pressure following coronary artery bypass grafting
Background. Cardiac surgery–related pulmonary complications include alterations in lung mechanics and anomalies in gas exchange. Higher levels of positive end–expiratory pressure (PEEP) have been suggested to benefit cardiac surgical patients. We compared respiratory compliance, arterial oxygenation and time till tracheal extubation in 2 cohorts of patients weaned from mechanical ventilation with different levels of PEEP after elective and uncomplicated coronary artery bypass grafting (CABG). We hypothesized that higher PEEP levels improve pulmonary compliance and gas exchange in the first hours of weaning from mechanical ventilation, but not to shorten time till tracheal extubation.
Materials and Methods. Secondary retrospective analysis of 2 randomized controlled trials: in the first trial patients were weaned with PEEP levels of 10 cmH2O for the first 4 hours followed by PEEP levels of 5 cmH2O until tracheal extubation (high PEEP, HP); and the second trial patients were weaned with PEEP levels of 5 cmH2O during the entire weaning phase (low PEEP, LP). The primary endpoint was pulmonary compliance. Secondary endpoints included arterial oxygenation, duration of mechanical ventilation and post-operative pulmonary complications.
Results. The analysis included 121 patients; 60 HP patients and 61 LP patients. Baseline characteristics were similar. Compared to LP patients, HP patients had a better pulmonary compliance, 47.2 ± 14.1 versus 42.7 ± 10.2 ml/cmH2O (P < 0.05), and higher levels of PaO2, 18.5 ± 6.6 (138.75 ± 49.5) versus 16.7 ± 5.4 (125.25 ± 40.5) kPa (mmHg) (P < 0.05). Patients in the HP group were less frequent in need of supplementary oxygen after ICU discharge. These differences remained present during the entire weaning phase, even after reduction of PEEP. However, HP patients had a longer time till tracheal extubation, 16.9 ± 6.1 versus 10.5 ± 5.0 hours (P < 0.001). HP patients had longer durations of postoperative infusion of propofol, 4.9 [2.6 – 7.4] versus 3.5 [1.8 – 5.8] hours (P < 0.05). There were no differences in use of inotropes. Cumulative fluid balances were slightly higher in HP patients.
Conclusion. Use of higher PEEP levels after elective uncomplicated CABG improves pulmonary compliance and oxygenation but seems to be associated with a delay in tracheal extubation.
PEEP following CABG
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Introduction
Pulmonary dysfunction is a ubiquitous consequence of cardiac surgery.1 Cardiac surgical patients are subjected to surgery–related factors, including sternotomy, cooling, the use of cardiopulmonary bypass and internal mammary artery dissection, which all predispose them to postoperative pulmonary complications. Cardiac surgery–related pulmonary complications include alterations in lung mechanics, anomalies in gas exchange, or both.1 Alterations in the mechanical properties of the lung lead to reductions in pulmonary compliance,2 vital capacity3 and functional residual capacity,4 which are reflected by immediate but short–lasting changes of the inspiratory pressure–volume curve of the respiratory system.5 Indeed, up to 4 hours after cardiac surgery the inspiratory pressure–volume curve has a sigmoid shape because of a right–shift of the lower inflection point (LIP) and a down–shift of the upper inflection point.
A positive end–expiratory pressure (PEEP) level set above the LIP may prevent atelectasis and decrease small airway closure.6,7 As such, higher PEEP levels could benefit cardiac surgical patients. However, higher PEEP levels could also have negative effects. Higher PEEP levels may cause caregivers to give more sedatives, which could lengthen the weaning process. In addition, higher PEEP levels may compromise cardiac output,8 mandating the use of more intravenous fluids to increase the afterload and inotropes to improve cardiac performance.
The aim of this study was to scrutinize the effects of higher PEEP levels on pulmonary function and weaning of cardiac surgical patients. We hypothesized that higher PEEP levels improve pulmonary compliance and gas exchange in the first hours of weaning from mechanical ventilation, but not to shorten time till tracheal extubation. Hereto we reanalysed and compared data from 2 randomized controlled trials of patients after elective and uncomplicated coronary artery bypass grafting (CABG) in which different PEEP levels were used.9,10
Methods
Study designIn this retrospective analysis, we analysed and compared prospectively collected respiratory parameters; times till tracheal extubation, prescriptions of sedatives and inotropes, and cumulative fluid balances from 2 randomized controlled trials of patients after CABG.9,10 The first trial was performed from October 2005 to July 2006,9 the second trial from August 2007 to August 2008.10 The mechanical ventilation protocol in the intervention arm of the first trial9 only differed from that in the control arm of the second trial10 with respect to the PEEP level used in the first 4 hours of weaning from mechanical ventilation (see below). In addition, we collected and compared need for supplementary oxygen and peripheral oxygen saturations in the ward, the presence or absence of infiltrates, atelectasis, pleural effusion and signs of fluid overload on chest X–rays, and the presence or absence of pneumonia.
SettingBoth trials recruited patients after CABG admitted to the 28–bed intensive care unit (ICU) of
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the Academic Medical Center, Amsterdam, the Netherlands. From October 2005 until August 2008 neither the medical staff nor the nursing staff changed. The medical staffing consisted of 8 full–time intensivists, 8 ICU fellows and 10 residents of other specialties, such as internal medicine, anaesthesiology and surgery. The nursing staff consisted of 140 qualified ICU nurses.
The protocols for anesthesia during surgery and post–operative care in the ICU were also left unaltered during conduct of both trials. In short, anesthesia started with 1 or 2 mg lorazepam as pre–medication, which was followed by etomidate, sufentanil and rocuronium for induction of anesthesia and facilitation of intubation. During the surgical procedure small doses of sufentanil were used as analgesic, and sevoflurane plus propofol were used to maintain anesthesia. Muscle relaxants were not given during the surgical procedure. Small boluses of morphine and midazolam could be given at the end of the procedure. Cardiopulmonary bypass was performed under moderate hypothermia (28 – 35°C), using a membrane oxygenator and non–pulsatile blood flow. At the end of anesthesia, all patients were transferred to the ICU with tracheal intubation. In the ICU fluid resuscitation existed of intravenous infusion of normal saline and starch solutions, and blood transfusion to maintain hemoglobin concentration (≥ 5.0 mmol/L or 190 g/l). Dopamine and norepinephrine were infused to achieve mean arterial pressure ≥ 70 mmHg, dobutamine and/or enoximone were infused to achieve a cardiac index ≥ 2.5 L/min/m2 or a mixed venous oxygenation > 60%. Propofol was given for sedation via continuous infusion until core temperature was > 36.00C. Acetaminophen (4 gram/day) was started in all patients. Morphine was given in small boluses of 1 to 2 mg intravenously at the descretion of attending ICU nurses. No neuromuscular blocking agents were used in the ICU.
The original trialsThe local institutional review board approved both trials, and preoperative written and signed informed consent was obtained from eligible patients programmed for elective CABG.
Inclusion and exclusion criteria were similar for both trials. In both trials we created a homogenous group of patients of ≥ 18 years after elective and uncomplicated CABG. Patients with a history of pulmonary disease or a history of pulmonary surgery were excluded; patients with an intra–aortic balloon pump or inotropes and/or vasopressors at a more then usual rate (in mg per hour): dopamine (16), norepinephrine (4), dobutamine (20) or epinephrine [any rate]) on arrival in the ICU were also excluded.
All patients were ventilated by Hamilton Galileo ventilators in the adaptive support ventilation (ASV) mode.11 (software version GMP03.41f, GCP03.40a, GTP01.00; Hamilton Medical AG, Rhäzüns, Switzerland). There were no differences in software versions between the original trails. Passive humidification of the ventilatory circuit was applied by means of a HME–filter (Medisize Hygrovent S, Medisize, Hillegom, The Netherlands). Minute ventilation was set at 100% of the theoretical value based on ideal body weight (IBW) (“100% minute ventilation”) and oxygen inspiratory fraction (FiO2) of 50%. Maximum airway pressure (P–max) was set 35 cmH2O (high–pressure pop–off). Flow trigger sensitivity was set at 2 L/sec. An arterial blood gas (ABG) analysis (Rapid Lab 865; Bayer Diagnostics, Dublin, Ireland) was performed 30 minutes after connection to the ventilator. If PaCO2 was < 3.5 kPa (26.25 mmHg) or > 5.5 kPa (41.25 mmHg) minute ventilation was adjusted. Any modification of the ventilator settings was advised to be
PEEP following CABG
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controlled after 30 minutes by a new ABG analysis. FiO2 was adjusted to maintain arterial oxygen saturation (SaO2) of ≥ 95%. The patient was extubated after achieving general tracheal extubation criteria (i.e., responsive and cooperative, urine output > 0.5 ml/kg/h, chest tube drainage < 100 ml last hour, no uncontrolled arrhythmia, rectal temperature > 360C, spontaneous respiratory frequency of 10–20 breaths per minute, futhermore a FiO2 of 40% and an inspiratory pressure (P–insp) of 5 to 10 cmH2O for 30 minutes.
PEEP level settingsIn the intervention group of the first trial,9 the PEEP level was set at 10 cmH2O in the first 4 hours after arival in the ICU, and therafter at 5 cmH2O until tracheal extubation (high PEEP, HP). In the control group of the second trial,10 the PEEP level was set at 5 cmH2O from admission to the ICU until tracheal extubation (low PEEP, LP).
Escape ventilation modeIn both trials pressure controlled and pressure support ventilation were indicated as escape ventilation if patients would fail weaning with ASV or afer reintubation.
Data collectionThe following data were collected: demographic data (gender, age, height, weight) operation characteristics (duration of anesthesia, duration of cardiopulmonary bypass, duration of cross–clamping).
Ventilation parameters (PEEP level, respiratory rate and tidal volume (VT), P–insp and dynamic compliance [all collected by a data logger (Hamilton data logger, version 3.27.1, Hamilton Medical AG connected to the ventilator], blood gas analysis results).
Outcome data (time till tracheal extubation, re–intubation, and length of stay in ICU [collected from the Patient Data Management System, IMDsoft, Sassenheim, the Netherlands]).
Other postoperative data: need of oxygen in the ward, rate of atelectasis at chest X-ray and pneumonia.
ICU data. Hourly fluid balances in three study fases, use of inotropics, opiod dose and types, midazolam dose, propofol dose. ICU discomfort data (use of physical restraints, the occurences of stress and/or agitation, as reported in medical and/or nursing reports).
Time phasesFor comparisons between groups, we defined 3 phases during stay in ICU. In HP patients, “phase–1” was the period during which patients were ventilated with a PEEP level of 10 cmH2O; “phase–2” was the period during which patients were ventilated with a PEEP level of 5 cmH2O (i.e., untill tracheal extubation); “phase–3” was the period from tracheal extubation untill discharge from the ICU. Phase–1 for LP patients was defined as the mean time of “phase–1” in HP patients; “phase–2” was the following period that ended with tracheal extubation; “phase–3” was the period from tracheal extubation untill discharge from the ICU.
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Table 1. Patient characteristics
Variable HP patients N = 63
LP patients N = 63
Gender, male (%) 55 (87) 55 (87)
Age, years 65 ± 8 64 ± 9
Actual body weight, kg 85 ± 14 83 ± 10
Predicted body weight, kg 71 ± 9 71 ± 8
Number of bypasses, N 3 [3 – 4] 3 [3 – 4]
Use of arterial graft, N (%) 51 (81%) 44 (70%)
Pump time, minutes 97 ± 33 103 ± 36
Aortic clamp time, minutes 59 ± 25 63 ± 27
Opiates OR – total dose, mg/kg 2.5 [1.8 – 3.4] 2.5 [2.0 – 3.1]
Benzodiazepines OR – total dose, mg/kg 1.7 [0.4 – 2.5] 1.8 [0.5 -2.8]
Length of stay in ICU, hours 25 [22 – 63] 27 [22 – 40]
HP: high positive end–expiratory pressure (PEEP); LP: low PEEP; ICU: intensive care unit; OR: Operation room. Data are means ± SD or medians [IQR]
HP: high positive end–expiratory pressure (PEEP); LP: low PEEP; IBW, ideal body weight; P–insp: inspiratory pressure; FiO2: fraction of inspiration oxygen. Data are means ± SD or medians [IQR]
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DefinitionsIdeal body body weight (IBW) was calculated by the following formula: in men, IBW (kg) = 50 + 0.91 X (centimeters of height - 152.4); in women, IBW (kg) = 45.5 + 0.91 X (centimeters of height - 152.4).12
Hourly cummulative fluid balances were calculated, ignoring insensible loss. Cumulative fluid balance was defined as the sum of all fluids (fluids in and out the patient) this was calculated per time-phase (see above). Inotrope doses were compared using a previously described inotrope score.13 The inotrope score was calculated as dopamine (x1) + dobutamine (x1) + milrinone (x15) + norepinephrine (x100).
Opiate doses were all recalculated as morphine equipotent doses with the following formula: 10 miligram (mg) of morphine = 0.1 mg fentanyl = 0.01 mg sufentanil.14 Doses of benzodiazepines were similary converted to equipotent doses of diazepam using the following formula: 5 mg midazolam = 10 mg diazepam = 50 mg oxazepam.15 Patient discomfort was defined as stress and agitation reported in the patient’s medical chart that led to an intervention such as administration of a benzodiazepine or mobilization.
We defined postoperative pneumonia as: new infiltrate(s) on the chest x-ray with leucocytes above 12 x109, fever (temperature above 38.3) and purulent sputum.
Statistical analysisDescriptive statistics were used to summarize patient characteristics. Categorical variables were compared between groups by chi–square tests. If normally distributed, continuous values are expressed as means ± standard deviation (SD), otherwise medians and interquartile ranges [IQR] were used. All analyses were performed in SPSS version 16.0 (SPSS inc., Chicago, IL).
Results
PatientsIn the original trials 64 patients were randomized to the intervention arm of the first trial9 and 64 patients to the control arm of the second trial.10 In both arms 1 patient was lost to analysis due to reaching exclusion criteria with respect to use of inotropes. Three HP patients and 2 LP patients were lost to analysis due to datalogger failure. This left us with 60 HP patients and 61 patients LP patients. Patient characteristics are shown in table 1. Patients from the 2 trials were well matched according to their baseline characteristics. No significant differences were found in baseline characteristics as well as in intra–operative medication requirements (aesthetics, opioids and benzodiazepines). Body temperature on arrival in the ICU was similar.
The PEEP level was set at 10 cmH2O for 5.0 ± 2.5 hours in HP patients, thereafter the PEEP level was maintained at 5 cmH2O until tracheal extubation. In LP patients PEEP levels were never set above 5 cmH2O.
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Table 3. Prescribed sedatives
Variable Phase HP patientsN = 60
LP patientsN = 61 p value
Total propofol dose, mg/kg
1 5.9 [3.0 – 9.7] 2.2 [5.2 – 8.0] 0.427
2 0 [0 – 4.0] 0 [0 – 2.1] 0.162
3 0 0 1
Propofol treatment, hours
1 4.9 [2.6 – 5.0] 3.5 [0.94 – 1.6] < 0.05
2 0 [0 – 2.5] 0 [0 – 1.0] 0.110
3 0 0 1
Total morfine dose, mg
1 0 [0 – 0] 0 [0 – 2.5] 0.390
2 0 [0 – 2.4] 0 [0 – 0] 0.199
3 0 [0 – 0] 0 [0 – 2.9] 0.064
Total benzodiazepines dose, mg
1 0 [0 – 0] 0 [0 – 0] 0.321
2 0 [0 – 0] 0 [0 – 0] 0.151
3 0 [0 – 0] 0 [0 – 0] 0.353
HP: high positive end–expiratory pressure (PEEP); LP: low PEEP. Data are means ± SD or medians [IQR]
Table 4. Discomfort data
Variable HP patientsN = 60
LP patientsN = 61 p value
Use of physical restraints, number of patients 9 3 0.06
Stress and/or agitation, number of patients 9 13 0.39
HP: high positive end–expiratory pressure (PEEP); LP: low PEEP. Data are means ± SD or medians [IQR]
Table 5. Inotrope scores and cumulative fluid balances
Variable Phase HP patientsN = 60
LP patientsN = 61 p value
Inotrope score
1 101 [15 – 115] 100 [5 – 115] 0.529
2 100 [100 – 115] 15 [0 – 115] 0.956
3 0 [0 – 0] 0 [0 – 0] 0.365
Cumulative fluid balance, ml
1 1112 ± 1108 1130 ± 999 0.928
2 776 ± 1127 507 ± 1054 0.198
3 643 ± 834 177 ± 738 < 0.05
HP: high positive end–expiratory pressure (PEEP); LP: low PEEP. Data are means ± SD or medians [IQR]
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While there were no HP patients who needed reintubation, 2 LP patients were reintubated after planned extubation (p = 0.87).
Both patients had to be reintubated, probably due to atelectasis both confirmed on chest x-ray after reintubation and ventilated with the escape ventilation modes pressure controlled and pressure support. Both patients were extubated in the subsequent course of their ICU stay.
Pulmonary complianceMechanical ventilation characteristics are presented in table 2. Compliance was higher in the HP patients in phase–1; although compliance remained higher in HP patients in phase–2, the difference did no longer reach statistical significance. VT was larger in HP patients in phase–1 and 2; P–insp was lower in phase–1 and 2, although differences did not reach statistical significance.
Arterial oxygenation and carbon dioxide levelsBlood gas analysis data are shown in figure 1. PaO2 levels were higher in HP patients in phase–1 and phase–2, but not in phase–3. In accordance, PaO2 to FiO2 ratios were higher in HP patients in phase–1, and remained significantly higher in phase–2. PaCO2 levels were lower in HP patients
Figure 1. Arterial oxygenation (PaO2), arterial carbon dioxide (PaCO2) and arterial pH, in phase–1, 2 and 3, and PaO2 to FiO2 ratios (P/F) in phase–1 and 2 after admission to ICUClosed symbols, patients ventilated with higher PEEP levels in phase–1; open symbols, patients ventilated with lower PEEP levels during the entire weaning period. *denotes statistical significant differences between groups
260
in phase–1 and phase–2. Arterial pH was similar between the 2 study groups, in all predefined phases. Patients in the HP group were less frequently in need for supplementary oxygen in the ward (relative risk of 0.80 (0.66 – 0.96), p-value of 0.02). Peripheral oxygen saturations in the ward were not different. There were no differences between groups regarding atelectasis, pleural effusion and signs of fluid overload at chest X–rays on day 1, two or three postoperatively. Two patients in the HP group developed pneumonia.
Duration of mechanical ventilationDuration of mechanical ventilation is shown in figure 2. Time from ICU admission to tracheal extubation was different between groups. HP patients were extubated after 16.9 ± 6.1 hours, while LP patients were extubated after 10.5 ± 5.0 hours (p < 0.001).
Sedatives and patient discomfortDose and duration of sedatives are shown in table 3. Discomfort data are shown in table 4. Median cumulative dose of propofol administered during stay in ICU tended to be higher in the HP patients, 8.5 [3.9 – 14.9] versus 5.8 [2.6 – 11.8] mg/kg (p = 0.16). In addition, propofol infusion was continued for a longer time, 4.9 [2.6 – 7.4] versus 3.5 [1.8 – 5.8] hours (p < 0.05). In phase–1 there was a significant difference between groups 4.9 [2.6 – 5.0] hours in the HP patients versus 1.6 [0.94 – 3.5] hours in the LP patients (p < 0.05). Opiates and benzodiazepines were seldom administered in both groups. Discomfort was not different between HP and LP patients.
Figure 2. Kaplan–Meier curve showing time until tracheal extubationClosed line, patients ventilated with higher PEEP levels in phase–1; Dotted line, patients ventilated with lower PEEP levels during the entire weaning period
HP: high positive end–expiratory pressure (PEEP); LP: low PEEP; N: number of patients; O2: Oxygen need on the ward; Antibiotics_pulm: Antibiotics prescribed for suspected pneumonia; n: number of occurrence; CXR: Chest X-ray abnormalities; Atelectasis on chest X-ray; Saturation: peripheral oxygen saturation in percentage
Inotropes and cumulative fluid balancesPrescription of inotropes and cumulative fluid balances are shown in table 5. The inotrope score was higher in HP patients in phase–2, but differences did not reach statistical significance. There were no clinically important differences between the 2 study groups with respect to cumulative fluid balances, although HP patients had a significant higher cumulative fluid balance at the end of stay in ICU.
Postoperative complicationsNeed of oxygen in the ward was significantly different between groups. Patients in the HP group were less frequent in need of supplementary oxygen in the normal ward, after ICU discharge (relative risk of 0.80 (0.66 – 0.96), p = 0.02). There were however no differences between groups regarding atelectasis at chest X-ray and other postoperative data (table 6). There were, according to our definition, two cases of pneumonia the HP group.
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Discussion
In this secondary analysis of 2 randomized controlled trials of patients after elective and uncomplicated CABG we determined the effects of use of higher PEEP levels on mechanical ventilation characteristics, including pulmonary compliance and oxygenation. The results can be summarized as follows: (1) compliance was higher in HP patients in phase–1, but not in phase–2; (2) oxygenation was better in HP patients in phase–1 and 2, but similar in phase–3; (3) time till tracheal extubation was longer in the HP patients and (4) Patients in the HP group needed supplementary oxygen after ICU discharge less frequently.
Our analysis confirms results from previous studies suggesting that higher PEEP levels improve pulmonary function after cardiac surgery.5–7 Indeed, with the use of higher PEEP levels pulmonary compliance was better and arterial oxygenation improved. Notably, the beneficial effect on pulmonary compliance was only found in phase–1, and the effect on arterial oxygenation disappeared after tracheal extubation. This latter finding is in accordance with findings of a previous observational study and randomized controlled trials.5,16,17 In one observational study of cardiac surgical patients, changes in lung mechanics were only present in the first hours after surgery.5 In a randomized controlled trail of patients after CABG, in which patients were mechanical ventilated with PEEP levels of 0, 5 or 10 cmH2O, it was shown that use of higher PEEP levels offered no sustained beneficial effect on arterial oxygenation or the occurrence of atelectasis on chest X–rays.16 In another randomized controlled trial of cardiac surgical patients, in which patients were mechanically ventilated with PEEP levels titrated on the best achievable PaO2 level, a similar course of the effects of PEEP over time was noted.17 It should be noted that patients in the HP group needed less frequently supplementary oxygen after ICU discharge. This may be because of prevention of atelectasis. Atelectasis may have been too small to be detected by chest X-rays, explaining why we did not find a difference between the study groups with regard to atelectasis on chest X–rays. Higher PEEP levels are frequently used in mechanically ventilated patients suffering from acute lung injury. Two recent metaanalyses of randomized controlled trials of patients with acute lung injury showed higher PEEP to be associated with a reduction in hospital mortality.18,19 Notably, this effect was only found in patients with more severe acute lung injury, since patients with less severe acute lung injury had no clinical benefit from the use of higher PEEP levels. Thus, the beneficial effects of PEEP seem to depend on the severity of illness. Obviously, short-lived pulmonary dysfunction, as found in patients after cardiac surgery, is different from abnormalities found in patients with acute lung injury.
We did not expect the PEEP level to have an effect on time till tracheal extubation after elective uncomplicated CABG. We found nevertheless a significant difference in time till extubation. Differences in the use of sedatives could explain differences in time to extubation. Sedation is often needed during the time the patients spend on the ventilator and are warming up, however oversedation can prolong this period and lead to adverse effects for the patient.20 We found that although the total dose of propofol was the same, the duration of the use of propofol was longer in the HP patients as well overall as in phase–1. This suggests that the use of higher PEEP leads to longer use of sedatives and this, in turn, could contribute to a longer duration of ventilation. However since the difference in time till extubation is much larger (almost 6 hours) then the difference in the time of the use of propofol (almost 1.5 hours) it is unlikely that the
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longer duration of the use of propofol explains the total difference in duration of ventilation. In a post hoc regression analysis we calculated that the attribution to the time till extubation of the duration of propofol infusion was 18% in the HP group and 8% in the LP group.
Another reason for the differences in duration of ventilation could be differences in the use of inotropes. However we found no differences in inotrope scores between HP and LP patients suggesting no influence of the applied PEEP level on the use of inotropes. Moreover it should be noted that although the protocol stated that HP should be given during 4 hours the mean duration of HP was 5 ± 2,5 h. The reason for this could be that PEEP was to be lowered according to the guideline when the patient was stable. Determining this could include a new blood gas analysis thus leading to delay.
As a high PEEP level may affect venous return, we expected a more positive fluid balance to maintain preload of the heart in the high PEEP group. Indeed, the ICU–guideline clearly advised to first infuse fluids before increasing the infusion rate of inotropics. A difference in fluid balances from ICU admission till tracheal extubation was not found. In both groups the fluid balance from ICU admission till tracheal extubation was approximately one liter, which is expected in patients who arrive in the ICU with mild hypothermia and sedation. The difference in fluid balance after tracheal extubation remains unexplained. Notably, the this difference was not associated with differences in oxygenation. In the postextubation period on the ward there were significant differences in the number of patients needing oxygen therapy. The LP group needed more oxygen. Whether or not this was caused by more atelectasis in this group as one would suspect is difficult to asses. The number of patients with atelectasis on there chest X-ray did not differ between the groups.
Although 2 patients in the HP group developed pneumonia, while no pneumonia was observed in the LP group, it should be noted that this difference was not statistically significant. If we added use of antibiotics for any cause (or the clinical diagnosis of pneumonia) to our definition no cases of pneumonia were present in both groups.
There are several limitations to our analysis. It should be recognized that the design of our study is not the most appropriate for comparison of two treatment strategies. This is an important drawback of our study, which should be taken into account when interpreting the study results. It would have been better to perform a randomized clinical trial to minimize the chances on bias and confounders.
Our analysis should be seen as a before–after study. It might be that our practice changed over time but that this change remained unnoted. However it should be said that the OR and ICU staff remained largely similar. Also, aside from the PEEP level used in mechanically ventilated patients after cardiac surgery, no changes were introduced in the local mechanical ventilation guideline. Moreover the question should be raised whether tracheal extubation of cardiac surgical patients is dependent on the ventilatory strategy e.g. PEEP levels alone or (also) on factors independent on the ventilation strategy. Anaesthesia and ICU teams may gain experience in the treatment of these patients, which could hasten tracheal extubation.21 Also, increased experience with the ventilation mode used in the two studies (Adaptive Support Ventilation) could have altered
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the treatment of these patients. It should be noted, however, that our team started the use of Adaptive Support Ventilation in 2004. And finally, better awareness of rather long weaning times in our institution could have led to a more proactive behaviour with regard to tracheal extubation.22
Another limitation is the titration of PEEP in our study. Notably, the PEEP level in our patients was not titrated on the LIP of individual pressure volume curves, since interpretation of pressure volume curves can be difficult and time consuming.23-27 We rather choose for a simple approach to use a PEEP level of 10 cmH2O for 4 hours, based on the findings in a previous observational study.5 This practical approach could have led to the use of too low PEEP levels. This in turn could have led to insufficient effect of the high PEEP strategy while in the meantime resulting in longer weaning times. Contrary our approach could also have led to unnecessary high levels of PEEP. Resulting in an exaggeration of the possible negative effects of higher PEEP levels and again to longer weaning times. Either way thus resulting in longer weaning times without the benefits of the use of higher PEEP levels.
While none of the HP patients needed to be reintubated, 2 LP patients had to be reintubated. Although this difference was not statistically significant, the finding is though–provoking. From the present analysis it cannot be concluded that the higher reintubation rate in LP patients is causally related to the PEEP level used in the first hours of weaning. However, since the 2 reintubated patients needed continuation of mechanical ventilation because of atelectasis, it can at least be speculated that the higher PEEP levels could prevent reintubation. It is legitimate to ask ourselves what is preferable: To extend few hours the period of weaning and prevent extubation failure or to shorten the routine weaning process and increase the risk of extubation failure? The fact that more LP patients used oxygen in the ward fits this picture as well. This hypothesis needs however to be tested in a well–powered randomized controlled trial
Conclusion
Use of higher PEEP levels after elective uncomplicated CABG improves pulmonary compliance and oxygenation but is associated with a delay in tracheal extubation.
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References1. Wynne R, Botti M. Postoperative pulmonary dysfunction in adults after cardiac surgery with cardiopulmonary bypass:
clinical significance and implications for practice. Am J Crit Care 2004; 13(5): 384-932. Chaney MA, Nikolov MP, Blakeman B, Bakhos M, Slogoff S. Pulmonary effects of methylprednisolone in patients
undergoing coronary artery bypass grafting and early tracheal extubation. Anesth Analg 1998; 87(1): 27-333. Johnson D, Hurst T, Thomson D, Mycyk T, Burbridge B, To T, Mayers I. Respiratory function after cardiac surgery. J
Cardiothorac Vasc Anesth 1996; 10(5): 571-74. Shapira N, Zabatino SM, Ahmed S, Murphy DM, Sullivan D, Lemole GM. Determinants of pulmonary function in patients
undergoing coronary bypass operations. Ann Thorac Surg 1990; 50(2): 268-735. Ranieri VM, Vitale N, Grasso S, Puntillo F, Mascia L, Paparella D et al. Time-course of impairment of respiratory
mechanics after cardiac surgery and cardiopulmonary bypass. Crit Care Med 1999; 27: 1454-606. McCarthy GS, Hedenstierna G. Arterial oxygenation during artificial ventilation. The effect of airway closure and of its
prevention by positive end-expiratory pressure. Acta Anaesthesiol Scand 1978; 22: 563-97. West JB. First annual SCCM lecture: pulmonary gas exchange in the critically ill patient. Crit Care Med 1974; 2: 171-808. Luecke T, Pelosi P. Clinical review: Positive end-expiratory pressure and cardiac output. Crit Care 2005; 9: 607-219. Dongelmans DA, Veelo DP, Paulus F, de Mol BA, Korevaar JC, Kudoga A et al. Weaning automation with adaptive support
ventilation: a randomized controlled trial in cardiothoracic surgery patients. Anesth Analg 2009; 108: 565-7110. Dongelmans DA, Veelo DP, Binnekade JM, de Mol BA, Kudoga A, Paulus F, Schultz MJ. Adaptive support ventilation
with protocolized de-escalation and escalation does not accelerate tracheal extubation of patients after nonfast-track cardiothoracic surgery. Anesth Analg 2010; 111(4): 961-7
11. Brunner JX. Iotti GA. Adaptive Support Ventilation (ASV). Minerva Anestesiologica 2002; 68(5): 365-36812. The Acute Respiratory Distress Syndrome Network.Ventilation with lower tidal volumes as compared with traditional
tidal volumes for acute lung injury and the acute respiratory distress syndrome. NEJM 2000; 342(18): 1301-813. Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR et al. Postoperative course and hemodynamic
profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 1995; 92: 2226-35
14. Reisine PG. The Pharmacological Basis of Therapeutics. Ninth Edition. ed. New York: McGraw-Hill, 199615. Wilson WC, Smedira NG, Fink C, McDowell JA, Luce JM et al. Ordering and administration of sedatives and analgesics
during the withholding and withdrawal of life support from critically ill patients. JAMA 1992; 267: 949-5316. Marvel SL, Elliott CG, Tocino I, Greenway LW, Metcalf SM, Chapman RH. Positive end-expiratory pressure following
coronary artery bypass grafting. Chest 1986; 90(4): 537-4117. Celebi S, Köner O, Menda F, Omay O, Günay I, Suzer K et al. The pulmonary and hemodynamic effects of two different
recruitment maneuvers after cardiac surgery. Anesth Analg 2007; 104: 384-9018. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS et al. Higher vs lower positive end-expiratory
pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and metaanalysis. JAMA 2010; 303(9): 865-73
19. Putensen C, Theuerkauf N, Zinserling J, Wrigge H, Pelosi P. Metaanalysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med 2009; 151(8): 566-76
20. Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest 1998; 114: 541-8
21. De Hert SG, Van der Linden PJ, Cromheecke S, Meeus R, ten Broecke PW, De Blier IG, Stockman BA, Rodrigus IE. Choice of primary anesthetic regimen can influence intensive care unit length of stay after coronary surgery with cardiopulmonary bypass. Anesthesiology 2004; 101(1): 9-20
22. Hawkes CA, Dhileepan S, Foxcroft D, Imberger G. Early extubation for adult cardiac surgical patients. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003587
23. Pestana D, Hernández-Gancedo C, Royo C, Una R, Villagrán MJ, Pena N, Criado A. Adjusting positive end-expiratory pressure and tidal volume in acute respiratory distress syndrome according to the pressure-volume curve. Acta Anaesthesiol Scand 2003; 47(3): 326-34
24. Jonson J, Svatensson C. Elastic pressure–Volume curves: what information do they convey? Thorax 1999; 54: 82–725. Lichtwark-Aschoff M, Mols G, Hedlund AJ, Kessler V, Markström AM, Guttmann J et al. Compliance is nonlinear over
tidal Volume irrespective of positive end-expiratory pressure level in surfactant-depleted piglets. Am J Respir Crit Care Med 2000; 162: 2125–33
26. Jonson B, Richard J-C, Straus C, Mancebo J, Lemaire F, Brochard L. Pressure-Volume curves and compliance in acute lung injury. Evidence of recruitment above the lower inflection point. Am J Respir Crit Care Med 1999; 159: 1172–78
27. Hickling KG. Best compliance during a decremental, but not incremental, positive end-expiratory pressure trial is related to open lung positive end-expiratory pressure. A mathematical model of acute respiratory distress syndrome lungs. Am J Respir Crit Care Med 2001; 163: 69–78
Chapter 12
Summary and general discussion
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Introduction
As an introduction to this chapter, we briefly summarize findings published before the writing of the thesis titled: ‘lung-protective perioperative mechanical ventilation’. A more extensive overview of this literature is provided in chapter 1.
Postoperative pulmonary complicationsSimilar to mechanical ventilation in critically ill patients, intraoperative ventilation has a strong potential to cause lung injury.1 Certain intraoperative ventilation settings are associated with the development of pulmonary complications after surgery.2 Occurrence of so–called postoperative pulmonary complications is strongly associated with clinical outcome.3
Ventilation–associated lung injuryIt is generally believed that overdistension and repetitive opening and closing of lung tissue are the two main mechanical causes of so–called ‘ventilation–associated lung injury’ (VALI).4 Use of too large tidal volumes could cause overdistension of lung tissue that remains aerated at the end of expiration, which could be aggravated by too high levels of positive end–expiratory pressure (PEEP). Too low levels of PEEP, though, could result in repetitive opening and closing of lung tissue that collapses at the end of expiration. Next to ‘mechanical stress’, ventilation could also cause ‘chemical stress’, as too high levels of fractional inspired oxygen (FiO2) can increase the production of reactive oxygen species (ROS),5 which have a direct toxic effect on lung cells. Too high levels of FiO2 could also increase the risk of resorption atelectasis.6 Lung-protective mechanical ventilation aims at low tidal volume ventilation to prevent overdistention, and higher levels of PEEP with recruitment manoeuvres to prevent repetitive collapse. Additionally, restrictive levels of FiO2 could protect against hyperoxia-induced lung injury.
Prevention of lung injury in critically ill patientsTwo large metaanalyses convincingly confirmed the results from randomized controlled trials in critically ill patients with the acute respiratory distress syndrome (ARDS) that showed ventilation with low tidal volumes to improve morbidity and mortality.7,8 While three randomized controlled trials in patients with ARDS individually showed no benefit of higher levels of PEEP,9-11 one individual patient data metaanalyses strongly suggest higher levels of PEEP to improve outcome of patients with moderate or severe ARDS.7
The evidence for benefit of using low tidal volumes in critical care patients without ARDS is less convincing, with only one randomized controlled trial in these patients showing a lower incidence of VALI during low tidal volume ventilation.12 One conventional metaanalysis13 and two individual patient data metaanalyses14,15 confirm these findings, but the quality of the included studies was sometimes low, hampering firm conclusions. Whether patients without ARDS benefit from higher levels of PEEP, is even more uncertain, with one trial suggesting benefit,16 one trial showing no effect,17 and one trial even suggesting harm.12
Clinical trials investigating the effect of hyperoxia on lung injury in critical care patients with or without ARDS are lacking, but high levels of FiO2 seem to have the potential to be harmful in other organs than the lung critically ill patients.18-21
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Prevention of lung injury in surgery patientsOne metaanalysis14 of patients without ARDS undergoing mechanical ventilation on the ICU or for surgery confirmed the findings of several clinical trials, suggesting that ventilation with lower tidal volumes decreases the occurrence of pulmonary complications and improves clinical outcomes. One problem with all these trials is that the investigators often combined the use of low tidal volumes with higher levels of PEEP,22-30 which makes it difficult if not impossible to determine the precise role of each single intervention on the beneficial effect. Some investigations suggest hyperoxia during intraoperative ventilation to have harmful effects,31, 32 but no clinical evidence on lung injury is available yet.
Summary of this thesis
The main aim of this thesis was to investigate the effect of intraoperative use of higher levels of PEEP, i.e., higher than the typical 0–2 cm H2O as applied by many anaesthesiologists, and recruitment manoeuvres on occurrence of postoperative pulmonary complications. We hypothesized that the use of higher levels of PEEP and recruitment manoeuvres would protect against development of postoperative pulmonary complications during low tidal volume ventilation. We further investigated several other aspects of perioperative ventilation, focussing on ventilation practice and the associations between ventilator settings and postoperative pulmonary complications and outcome. In this chapter we summarize the results of the studies presented in this thesis, describes how these results can be placed in context of previous research findings, and speculates on future perspectives.
In Chapter 2 we describe a metaanalysis examining the effects of intraoperative ventilator settings on postoperative outcome of non–cardiac surgery patients.33 In this analysis we tried to separate the effects of tidal volume reduction and of higher levels of PEEP on postoperative complications. We hypothesized that low tidal volumes and higher levels of PEEP with or without recruitment manoeuvres could both prevent postoperative pulmonary complications. In the analysis of eight clinical trials comprising of 1669 patients, ventilation with lower tidal volumes was associated with a lower incidence of postoperative lung injury, pulmonary infections and atelectasis compared to ventilation with conventional tidal volumes. For the examination of settings for PEEP, only five of eight trials (1323 patients) were suited for the analysis, comparing ventilation without or with lower levels of PEEP with higher levels of PEEP during surgery. Patients ventilated with higher levels of PEEP developed less postoperative lung injury and atelectasis. A beneficial effect of high levels of PEEP on postoperative pulmonary infection was also found, but in this analysis there was moderate heterogeneity. We did not find trials investigating exclusively the effects of intraoperative recruitment manoeuvres. It should be taken into account that the five trials assessing the effect of ventilation with higher levels of PEEP and recruitment manoeuvres were also part of the metaanalysis on the effect of ventilation with lower tidal volumes. In this analysis it remained uncertain whether the use of high PEEP, with or without recruitment manoeuvres, added to the beneficial effects of intraoperative use of lower tidal volumes.
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In Chapter 3 we more extensively review the literature on intraoperative protective ventilatory strategies to prevent postoperative pulmonary complications.34 We describe six studies on predictive models of postoperative pulmonary complications, eleven trials on protective ventilation during general anaesthesia for surgery with a nonclinical primary outcome, and eight trials with a clinical primary outcome. We determined that increasing evidence shows that intraoperative lung-protective mechanical ventilation decreases the risk of postoperative pulmonary complications. However, the precise role of each single intervention remains uncertain. We conclude this review with a recommendation on intraoperative lung-protective ventilation and propose a new, alternative ventilation strategy during general anaesthesia: “permissive atelectasis”. In this new approach patients are ventilated with relatively low levels of PEEP and without recruitment manoeuvres, which reduces static stress in the lungs. Permissive atelectasis, however, could cause perioperative hypoxia, which can be counteracted by increasing in the inspired oxygen fraction.
Chapters 4 and 5 present an international prospective observational study aiming to describe current ventilator practice regarding intraoperative ventilation, and to determine any association between ventilator settings and incidence of postoperative pulmonary complications.35 We hypothesised that low tidal volumes and high levels of PEEP were commonly used, and that both are associated with a reduced incidence of postoperative pulmonary complications. During a seven–day period, data of 8,327 consecutive adult patients requiring invasive ventilation during general anaesthesia for surgery from 146 centres worldwide was collected. Intraoperative ventilation settings and postoperative data on pulmonary complications up to day 5 were collected. Our results show that patients are generally ventilated with relatively low tidal volumes (median of 500.0 [454.2 – 550.5] mL or 8.1 [7.2 – 9.1] mL/kg PBW), PEEP levels of 4.0 [0.0 – 5.0] cmH2O, and that recruitment manoeuvres are rarely performed (9.5%). The chosen level of tidal volume represents the default settings on many anaesthesia ventilators, suggesting a lack of individualisation. Postoperative pulmonary complications occurred frequently after surgery (10.4%), and were associated with longer length of hospital stay and mortality. In two different multivariate models we found that the use of higher levels of PEEP, but not size of tidal volume was independently associated with increased development of postoperative pulmonary complications.
In Chapter 6 we describe the results of an individual patient data metaanalysis using data from 15 randomized controlled trials of intraoperative ventilation.36 We tested the hypothesis that intraoperative ventilation with lower tidal volumes protects against postoperative pulmonary complications and improves clinical outcome, and that use of higher levels of PEEP adds to the beneficial effects of lower tidal volumes. The results from 2,127 patients show that intraoperative protective ventilation strategies have beneficial influence on incidence of postoperative pulmonary complications, but they did not have an effect on length of stay or mortality. Patients that developed a pulmonary complication postoperatively did have longer lengths of ICU and hospital stay and increased mortality rates. In the analysis of the individual effect of intraoperative low tidal volumes, we found decreased incidence of postoperative pulmonary complications. If higher levels of PEEP were added to low tidal volume ventilation, this did not attribute to additional benefit. The analysis on the individual effect of PEEP did not show significant influence on development of postoperative pulmonary complications.
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In Chapters 7, 8 and 9 we present an international trial comparing PEEP levels of 12 cmH2O combined with recruitment manoeuvres to PEEP levels of 2 cmH2O without recruitment manoeuvres in non-obese patients at high risk for postoperative pulmonary complications planned for open abdominal surgery with ventilation at tidal volumes of 8 mL/kg.37-39 In this trial we tested the hypothesis that a ventilation strategy with high levels of PEEP and recruitment manoeuvres protects against development of postoperative pulmonary complications. We randomized 900 patients from 30 centres throughout Europe and the Americas. The incidence of postoperative pulmonary complications in the first 5 days after surgery did not differ between patients receiving protective ventilation or non-protective ventilation. Patients receiving higher levels of PEEP more frequently developed intraoperative hypotension and needed more vasoactive drugs. In the lower PEEP group, the incidence of intraoperative desaturations was higher. The results of this trial indicate that protective ventilation with low tidal volumes does not gain from higher levels of PEEP with recruitment manoeuvres and may even impair hemodynamics.
In Chapter 10 we investigated whether development of postoperative lung injury attributes to incidence of morbidity and mortality, by performing a second metaanalysis using individual patient data from 12 investigations of intraoperative ventilation.40 We hypothesized that the occurrence of postoperative lung injury would be associated with worse outcome, and that postoperative outcome depends on intraoperative ventilation settings. In 3365 patients development of postoperative lung injury increased the risk of mortality, especially in patients submitted to thoracic procedures compared to abdominal procedures. The incidence of lung injury was similar between thoracic and abdominal surgery. Development of lung injury was associated with longer ICU and hospital lengths of stay. When examining the intraoperative ventilation strategies, protective ventilation was associated with lower incidence of postoperative lung injury, but not with reduced mortality rates. Also in the event of postoperative lung injury, the previously applied protective strategy of ventilation was not associated with reduced attributable mortality. This suggests that the benefits of intraoperative protective ventilation are restricted to the reduction of development of postoperative lung injury.
In Chapter 11 we extend our research from the operation room to patients ventilated in the intensive care unit after surgery. In a secondary analysis of two previous trials in patients undergoing elective and uncomplicated coronary artery bypass grafting (CABG),41, 42 we investigated the effects of PEEP on pulmonary compliance and gas exchange in the first hours of weaning from mechanical ventilation and total time on the ventilator.43 We hypothesized that higher levels of PEEP improves pulmonary function, but does not shorten duration of postoperative ventilation. We found in 121 patients that ventilation with higher levels of PEEP resulted in better compliance and oxygenation. The beneficial effect on pulmonary compliance during ventilation was only sustained when PEEP levels were kept above 5 cmH2O. After tracheal extubation the positive effect on both compliance and arterial oxygenation was not maintained. Nonetheless, patients ventilated with higher levels of PEEP required less supplemental oxygen on the ward, which could indicate that these patients had less atelectasis. Time on the ventilator was longer in patients ventilated with higher levels of PEEP. One partial explanation could be that these patients received infusion of hypnotics during a longer period of time.
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General discussion
The main finding of this thesis is that intraoperative ventilation with higher levels of PEEP does not seem to reduce development of postoperative pulmonary complications during low tidal volume ventilation (chapter 6 and 8), in non-obese patients undergoing major surgery (cardiac, thoracic, abdominal, or spine surgery). High levels of PEEP may even be detrimental by causing hemodynamic compromise (chapter 8) and maybe even by increasing the risk of postoperative pulmonary complications (chapter 5).
In this thesis, we further show that lung-protective strategies using low tidal volumes combined with higher levels of PEEP reduce the incidence of postoperative pulmonary complications (chapters 2, 3, 6 and 10), but do not shorten hospital length of stay, or improve survival (chapters 6 and 10). In the event of a pulmonary complication, patients do have longer lengths of ICU and hospital stay, and have a higher incidence of mortality (chapter 5, 6 and 10). Finally, use of higher levels of PEEP during postoperative ventilation resulted in better compliance and oxygenation in patients undergoing elective and uncomplicated coronary artery bypass grafting, but this was not sustained after extubation and time to extubation was increased (chapter 11).
PEEP may not be beneficialContrary to general belief, this thesis shows that ventilation with higher levels of PEEP may not attribute to the protective effect of low tidal volumes on the development of postoperative pulmonary complications. Individual patient data analysis found no increased benefit of higher levels of PEEP in patients ventilated with low tidal volumes on development of pulmonary complications (chapter 6).36 Additionally, the analysis of dose–response relationship in this study suggests that there is neither a positive, nor a negative association between a higher level of PEEP and the development of postoperative pulmonary complications. In postoperative cardiac surgery patients, ventilation with higher levels of PEEP did not have a sustained effect on pulmonary compliance or arterial oxygenation (chapter 11).43 The PROVHILO trial showed that levels of 12 cmH2O PEEP did not protect against development of postoperative complications during low tidal volume ventilation (chapter 8).38 The chosen level of PEEP in this trial was criticized, because it is higher than normally applied in clinical practice.44 The resulting high end-inspiratory pressures might have caused overinflation of normally aerated alveoli. This could have diminished the clinical benefits of ventilation with higher PEEP levels. However, the level of PEEP was based on previous investigations, recommending a minimal level of 10 cmH2O PEEP to prevent cyclic opening and closing of alveoli during intraoperative ventilation.45-47 Indeed, as mentioned in our Author’s reply (chapter 9),39 the higher PEEP group showed increasing dynamic compliance during intraoperative mechanical ventilation. This suggests that effective lung recruitment was achieved, without overt overdistention. On the other hand, peak airway pressures were increased in the higher PEEP group, suggesting increased alveolar pressures that could have contributed to hyperinflation.
Experimental and clinical studies have previously questioned the beneficial effects of PEEP. As far back as the ‘70s, studies in dogs with injured lungs found that application of a level of 10 cmH2O PEEP compared to no PEEP did not counteract formation of oedema fluid, when inspiratory pressure levels were kept equal.48, 49 In pigs with non-injured lungs no difference in inflammatory
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response was seen between high and low levels of PEEP during low tidal ventilation.50 When examining the alveoli up-close with in vivo microscopy in pigs with surfactant deactivated lungs, alveolar stability did not differ when PEEP was set a different levels.51
In critical care patients with ARDS, no additional protective effect of higher PEEP levels was seen in mild ARDS.7 In critical care patients without ARDS, high PEEP had very limited beneficial effect on the lungs.16, 17 During intraoperative ventilation no significant beneficial effect of PEEP level above 5 cmH2O was seen on development of postoperative pulmonary complications in a retrospective study.52
PEEP may cause harmUse of higher levels of PEEP may even cause harm. High levels of PEEP can compromise intraoperative hemodynamics (chapter 8).38 Furthermore, use of PEEP may be associated with increased risk of postoperative pulmonary complications (chapter 5). In patients mechanically ventilated after CABG, high levels of PEEP prolonged weaning from the ventilator (chapter 11).43
The undesirable effect of high levels of PEEP on hemodynamics has been identified in previous investigations.53, 54 The negative effects of high levels of PEEP on development of pulmonary complications seem to be in contrast to recent clinical trials.24, 55, 56 A possible explanation could be that compared to these studies, the tidal volume size reported in chapter 5 was much smaller. Notably, the LAS VEGAS study found no association between tidal volume size and development of pulmonary complications. In the event of low tidal volume ventilation, higher levels of PEEP could attribute to hyperinflation of normally aerated lung areas and possibly augment intra-tidal shear stress of collapsed lung areas.
Earlier animal and human studies have described the potential harm of ventilation with high levels of PEEP. In healthy rats receiving low tidal volume ventilation, high levels of PEEP (15 cmH2O) caused more pulmonary oedema than levels of 0 or 10 cmH2O PEEP.57 In a surgical model of pigs without lung injury, high levels of PEEP were associated with increase of pulmonary inflammation.58 When examining different areas of rat-lung after surfactant depletion and injurious ventilation, alveolar injury was higher in the alveoli that remain open during the complete breath cycle, compared to the alveoli that collapse at end-expiration.59
In mechanically ventilated patients with acute lung injury PET-CT scans showed maximum metabolic activity in the normally aerated lung regions, and no increase in metabolic activity in regions undergoing cyclic opening and closing.60
The degree of metabolic activity in the aerated regions was associated with higher plateau pressures. This was also seen in a recent retrospective study in surgical patients, showing a strong association between reduction in plateau pressure and a decrease in postoperative pulmonary complications.52 These results suggest that even though higher levels of PEEP may lessen atelectasis formation, due to the consequential high plateau pressures normally aerated alveoli may become overdistended.
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Driving pressureExperimental studies confirm that ventilation with higher plateau pressures can be injurious (so-called stress), but suggest that repetitive deformation during the respiratory cycle can cause more injury to the lung (so-called strain).61-64 The maximal deformation of the lung during mechanical ventilation is best expressed by calculating the driving pressure: plateau pressure minus positive end-expiratory pressure. In mechanically ventilated rats, driving pressure appeared to be one of the most important ventilation factors for lung injury.57 In studies in patients with ARDS a possible association between driving pressure and poorer outcome was identified.65-67 In a large individual patient data metaanalysis on patients with ARDS receiving protective ventilation, driving pressure was the ventilation parameter that was strongest associated with mortality.68
Functional lung sizeDriving pressure is intrinsically connected to respiratory system compliance. To inflate the lung up to tidal volume (VT), a certain pressure increase is required: the driving pressure (∆P). The amount of pressure necessary to inflate the lung depends on the compliance of the respiratory system (C = VT/∆P). Lung compliance is strongly related to the volume of the remaining aerated lung, when functional lung volume is reduced (termed functional lung size). Normalization of tidal volume to functional lung size results in driving pressure (∆P=VT/C). This is different to the generally used normalization to predicted body weight (mL/kg). The former adjusts for a possible decrease in lung aeration, while the latter corresponds with lung size of healthy, spontaneously breathing persons.
Functional lung size is decreased in patients with ARDS and in patients with healthy lungs undergoing mechanical ventilation. In ARDS, the diseased lung causes a decrease in compliance, while in patients with healthy lungs induction of anaesthesia or sedation causes large portions of the lung to collapse.69 In mechanically ventilated patients driving pressure may therefore better represent lung size, than lung size corrected for predicted body weight.
PEEP and driving pressure The effects of the level of PEEP on compliance and driving pressure are complex. In patients with decreased compliance two different phenomena may simultaneously occur when levels of PEEP are increased. First, increased levels of PEEP prevent the lung from collapsing, thereby reducing the amount of lung tissue undergoing repeated/cyclic opening and closing. This increases functional lung size and compliance, and decreases driving pressure. Second, if the higher levels of PEEP do not effectively prevent atelectasis formation, end-inspiratory pressures and transpulmonary pressures will increase and result in hyperinflation of the aerated portion of the lung.62, 69, 70 The optimum of this delicate balance in prevention of alveolar stress and strain remains unsure and quite possibly differs considerably per patient. Further investigations are warranted, to provide individually tailored mechanical ventilation guidelines for each patient.
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Summary and general discussion
Future perspectives
Individual PEEP titrationThe findings of this thesis suggest that setting one fixed level of PEEP may not be beneficial for all surgical patients in general. An improvement could be to focus more on individualized patient care, and titrate levels of PEEP on patient-specific parameters to minimize ventilator-associated lung injury. Previous studies have titrated “best PEEP” per individual patient by searching for the highest level of PEEP that optimizes aeration and avoids cyclic opening and closing of alveoli. This thesis suggests that high levels of PEEP may be harmful to the lung. Titration of levels of PEEP should therefor focus on “lowest PEEP”, to prevent hyperinflation of patent alveoli, while avoiding severe desaturation.
Several methods have been described to titrate levels of PEEP on patient-specific physiologic parameters. Many were based on oxygenation parameters,71-76 but these correlate poorly with the amount of lung recruitment77, 78 and cannot indicate hyperinflation.
One method to titrate PEEP, is by oesophageal pressure measurement.79 By determining the oesophageal pressure, transpulmonary pressures can be calculated and used to titrate PEEP. Nonetheless, this method was primarily tested in critical care patients with ARDS. The technique is not easily transferred to the surgical population, where pneumoperitoneum and extreme positioning frequently occur and could severely alter the oesophageal pressure measurements. Furthermore, even though they seem to be strongly related, oesophageal pressures do not equal pleural pressures.80, 81
Another method is electric impedance tomography (EIT), which can image and evaluate regional distribution of alveolar aeration.82-84 With EIT the lowest levels of PEEP could be titrated by examining the aerated regions of the lung for signs of hyperinflation.85-87 Even though EIT seems to be a monitoring system with potential in experimental and clinical studies, it is not applied in clinical routine yet.
As mentioned previously, increased driving pressures seem to be strongest correlated with increased lung injury and mortality.65-68 Driving pressures may therefore be the most suitable global ventilation parameter to guide individual PEEP titration. However, the studies investigating driving pressure are all of retrospective design and performed post hoc analyses. Whether driving pressure can be manipulated at the bedside, and whether it is indeed associated with lung injury, needs to be tested in clinical trials.
Permissive atelectasisIn surgical patients with healthy lungs titration to the lowest levels of PEEP may not be necessary. Level of PEEP can be set at zero or low levels, as long as inspiratory volumes and pressures are kept within range.88, 89 In chapter 3 we proposed a new ventilation strategy termed “intraoperative permissive atelectasis”.34 This approach combines intraoperative low tidal volume ventilation with relatively low levels of PEEP without recruitment manoeuvres. If hypoxemia (SpO2 ≤ 92%) develops the FiO2 should be increased first, followed by increase of levels of PEEP, and recruitment manoeuvres based on stepwise increase of tidal volume during regular mechanical ventilation.
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Experimental and clinical studies have shown that during ventilation with levels of low or zero PEEP inflammation is less in lung regions with atelectasis than in the normally aerated portions of the lung,51, 59-61 supporting the theory of permissive atelectasis. Permissive atelectasis could be a simple, acceptable method to reduce global strain in the lung and reduce alveolar hyperinflation during intraoperative low tidal volume ventilation in surgical patients with healthy lungs.
In conclusion
The main finding of this thesis is that intraoperative ventilation with higher levels of PEEP does not seem to reduce development of postoperative pulmonary complications during low tidal volume ventilation. Use of higher levels of PEEP may even cause harm. High levels of PEEP can compromise intraoperative hemodynamics. Furthermore, use of PEEP may be associated with increased risk of postoperative pulmonary complication.
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41. Dongelmans DA, Veelo DP, Paulus F, et al. Weaning automation with adaptive support ventilation: a randomized controlled trial in cardiothoracic surgery patients. Anesthesia and analgesia 2009; 108(2): 565-71
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43. Dongelmans DA, Hemmes SN, Kudoga AC, Veelo DP, Binnekade JM, Schultz MJ. Positive end-expiratory pressure following coronary artery bypass grafting. Minerva anestesiologica 2012; 78(7): 790-800
44. Futier E. Positive end-expiratory pressure in surgery: good or bad? Lancet 2014; 384(9942): 472-445. Brismar B, Hedenstierna G, Lundquist H, Strandberg A, Svensson L, Tokics L. Pulmonary densities during anesthesia
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48. Hopewell PC. Failure of positive end-expiratory pressure to decrease lung water content in alloxan-induced pulmonary edema. The American review of respiratory disease 1979; 120(4): 813-9
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50. Hong CM, Xu DZ, Lu Q, et al. Systemic inflammatory response does not correlate with acute lung injury associated with mechanical ventilation strategies in normal lungs. Anesthesia and analgesia 2012; 115(1): 118-21
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73. Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. American journal of respiratory and critical care medicine 1998; 158(6): 1831-8
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75. Murray IP, Modell JH, Gallagher TJ, Banner MJ. Titration of PEEP by the arterial minus end-tidal carbon dioxide gradient. Chest 1984; 85(1): 100-4
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77. Dantzker DR, Lynch JP, Weg JG. Depression of cardiac output is a mechanism of shunt reduction in the therapy of acute respiratory failure. Chest 1980; 77(5): 636-42
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82. Costa EL, Borges JB, Melo A, et al. Bedside estimation of recruitable alveolar collapse and hyperdistension by electrical impedance tomography. Intensive care medicine 2009; 35(6): 1132-7
83. Meier T, Luepschen H, Karsten J, et al. Assessment of regional lung recruitment and derecruitment during a PEEP trial based on electrical impedance tomography. Intensive care medicine 2008; 34(3): 543-50
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86. Karsten J, Grusnick C, Paarmann H, Heringlake M, Heinze H. Positive end-expiratory pressure titration at bedside using electrical impedance tomography in post-operative cardiac surgery patients. Acta anaesthesiologica Scandinavica 2015; 59(6): 723-32
87. Blankman P, Hasan D, Erik G, Gommers D. Detection of ‘best’ positive end-expiratory pressure derived from electrical impedance tomography parameters during a decremental positive end-expiratory pressure trial. Critical Care 2014; 18(3): R95
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Appendices
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Introductie
Postoperatieve pulmonale complicatiesTijdens en na operaties wordt de ademhaling van patiënten vaak tijdelijk geregeld middels een beademingsmachine (mechanische ventilatie). De belangrijkste instellingen van de beademingsmachine hebben betrekking op de druk waarmee lucht wordt ingeblazen en het volume dat wordt ingeblazen. Suboptimale instellingen kunnen schade aan de long veroorzaken.1 Dit vergroot waarschijnlijk het risico op het ontwikkelen van postoperatieve complicaties met betrekking tot de longen2 en kan het klinisch herstel doen verslechteren.3 Toch is het niet geheel duidelijk wat precies de beste instellingen zijn.
Longschade door mechanische ventilatieEr zijn meerdere mechanismen beschreven die tijdens mechanische beademing de long kunnen beschadigen. De twee belangrijkste mechanismen zijn het overrekken van longblaasjes aan het einde van de inademing en het herhaaldelijk openen en sluiten van longblaasjes die samenvallen tijdens de uitademing.4 Het gebruik van te hoge drukken tijdens de inademing of te grote volumes bij een ademteug (teugvolumes), kan overrekking van longblaasjes veroorzaken. Dit kan verergerd worden door te hoge drukken aan het einde van de uitademing (positive end–expiratory pressure, PEEP). Echter, wanneer de PEEP drukken te laag zijn, kan dit resulteren in herhaaldelijk openen en sluiten van longblaasjes tijdens de ademcyclus. Naast deze ‘mechanische stress’ ondergaat de long ook ‘chemische stress’ tijdens mechanische beademing. Een hoog percentage zuurstof (FiO2) in de inademingslucht verhoogt de aanmaak van zogenaamde reactieve zuurstofradicalen, wat schadelijk is voor de cellen.5 Een hoog percentage FiO2 (> 0.8) verergert tevens het samenvallen van longblaasjes (atelectase), omdat zuurstof heel snel wordt opgenomen door het lichaam.6 Op grond van deze mechanismen, bestaat long-beschermende beademing uit beademing met lage teugvolumes om overrekking van longblaasjes te voorkomen en met positieve drukken aan het einde van de expiratie (PEEP) om repetitief openen en sluiten van longblaasjes te vermijden. Hier kunnen nog zogenaamde rekruteer manouvres aan worden toegevoegd. Met deze techniek wordt geprobeerd samengevallen longblaasjes weer te openen. Lagere concentraties zuurstof zouden daarbij kunnen beschermen tegen longschade door het voorkomen van een te hoog zuurstofgehalte in de longen en het bloed.
Long-beschermende beademing van patiënten op de Intensive CareBij patiënten met acute respiratory distress syndrome of ARDS (een ernstige longaandoening dat gekenmerkt wordt door een heftige ontstekingsreactie in de longen) is uit gerandomiseerde onderzoeken gebleken dat lage teugbeademing de incidentie van longschade en zelfs sterfte vermindert. Dit is bevestigd door twee grote metaanalyses.7, 8 Beademing met hogere PEEP niveaus liet in drie verschillende trials geen beschermend effect zien bij patiënten met ARDS,9-
11 terwijl op grond van een grote meta-analyse hogere PEEP niveaus wel bescherming lijken te bieden bij patiënten met matige of ernstige ARDS.7
Bij patiënten op de Intensive Care zonder ARDS is het bewijs voor het beschermende effect van lage teugen minder sterk. De auteurs van een gerandomiseerde trial concluderen dat het
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gebruik van lage teugvolumes resulteert in een lagere incidentie van longschade.12 Dit is bevestigd door een conventionele meta-analyse13 en twee metaanalyses waarbij individuele patiëntdata werden gebruikt.14, 15 De geïncludeerde studies in deze metaanalyses waren echter van matige kwaliteit, waardoor de uitkomsten met enige voorzichtigheid dienen te worden geïnterpreteerd. Voor het gebruik van PEEP bij patiënten op de Intensive Care zonder ARDS is weinig onderzoek beschikbaar en worden tegenstrijdige resultaten gerapporteerd. De resultaten van een trial suggereerden een beschermend effect van hogere PEEP niveaus,16, 17 in een trial werd geen effect gevonden12 en de auteurs van een trial stelden zelfs nadelige effecten vast.12 Er zijn geen klinische trials beschikbaar met de schadelijke effecten van een hoog percentage O2 op de longen als onderwerp. Een hoog percentage O2 lijkt wel schade te kunnen veroorzaken in andere organen, bij beademende patiënten met of zonder ARDS op de Intensive Care.18-21
Long-beschermende beademing in chirurgische patiënten Het potentieel beschermende effect van long-protectieve beademing op de Intensive Care wakkerde interesse aan voor long-beschermende beademing ook toe te passen rondom operaties. De laatste jaren zijn verschillende studies naar beademing van chirurgische patiënten op de operatiekamer verricht. Studies naar lage teugbeademing, stelden vast dat de incidentie van postoperatieve complicaties daalde en het klinisch beloop verbeterde.22-24 Andere studies combineerden lage teugen met hogere PEEP niveaus en vonden ook een verbeterde uitkomst.25-33 Een grote meta-analyse van studies naar long-beschermende beademing in patiënten zonder longschade die beademend werden op de Intensive Care of tijdens chirurgie bevestigt deze resultaten.14 Bij veel van deze studies is het echter moeilijk om te onderscheiden welk element het beschermende effect veroorzaakte: lage teugen of hogere PEEP niveaus, of rekruteer manoeuvres, of een combinatie van deze drie. Klinische studies naar het schadelijke effect van een hoog zuurstofpercentage op de longen zijn niet beschikbaar, maar ook in deze patiënten lijken hoge zuurstoffracties schadelijk.34, 35
Samenvatting van dit proefschrift
Doelen proefschriftDit proefschrift, genaamd long-beschermende beademing rondom en tijdens operaties, richt zich op verschillende aspecten van beademing tijdens en na een operatie, met name op de klinische praktijk en de associaties tussen verschillende beademingsinstellingen en postoperatieve complicaties van de longen. De focus hierbij ligt vooral op PEEP, waarbij wij het effect van intra-operatieve beademing met hogere PEEP niveaus en rekruteer manoeuvres op ontwikkelen van postoperatieve pulmonale complicaties tijdens lage teugbeademing gedurende open buik chirurgie onderzochten. Onze hypothese was dat het gebruik van hogere PEEP niveaus met rekruteer manoeuvres zou beschermen tegen het ontwikkelen van postoperatieve pulmonale complicaties.
SamenvattingHoofdstuk 1 bestaat uit een algemene introductie, waarin de literatuur gepubliceerd voor het uitvoeren van de studies in dit proefschrift wordt samengevat. Hoofdstuk 2 bevat een meta-
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analyse van acht klinische studies die de effecten van intra-operatieve beademingsinstellingen op postoperatieve uitkomsten vaststelden bij patiënten die niet-cardiale chirurgie ondergingen.36 Hierbij poogden wij onderscheid te maken tussen de effecten van lage teugen en van hogere PEEP niveaus. Onze hypothese was dat zowel lage teugen als hogere PEEP niveaus met of zonder rekruteer manoeuvres het ontwikkelen van postoperatieve pulmonale complicaties kon voorkomen. In een populatie van 1669 patiënten was beademing met lage teugen geassocieerd met minder postoperatieve long schade, longontsteking en atelectase, vergeleken met conventionele beademing. In de meta-analyse met als onderwerp PEEP, konden maar vijf van de acht onderzoeken worden meegenomen (1323 patiënten). In deze vijf onderzoeken werden lage PEEP niveaus (0 tot 3 cmH2O) met hogere PEEP niveaus (3 – 12 cmH2O) vergeleken. Patiënten die met hogere PEEP niveaus werden beademend ontwikkelden minder postoperatieve longschade en atelectase. Daarbij hadden zij minder vaak een longontsteking, al was er sprake van enige heterogeniteit in deze analyse. Er waren geen trials beschikbaar die specifiek rekruteer manoeuvres onderzochten. Een punt van aandacht is dat de vijf studies naar PEEP niveaus in de meta-analyse ook deel waren van de meta-analyse naar lage teugvolumes. Daardoor blijft het in deze analyse onzeker of hogere PEEP niveaus met of zonder rekruteer manoeuvres bijdragen aan het beschermde effect van lage teugbeademing.
Hoofdstuk 3 bevat een uitgebreider overzicht van de literatuur over intra-operatieve beschermende beademing.37 Wij beschrijven hierin zes studies naar preoperatieve voorspellende modellen van postoperatieve pulmonale complicaties, 11 studies naar beschermende beademing tijdens algehele anesthesie met een niet-klinisch primair eindpunt en acht studies naar beschermende beademing met een klinisch primair eindpunt. Uit deze studies concluderen wij dat er toenemend bewijs is dat intra-operatieve long-beschermende beademing het risico op postoperatieve pulmonale complicaties vermindert. De exacte bijdrage van de afzonderlijke elementen (teugvolume, PEEP en rekruteer manouvres) bij long-beschermende beademing blijft echter onduidelijk. Wij sluiten het overzicht af met een voorstel voor een nieuwe benadering van intra-operatieve long-beschermende beademing: ‘permissive atelectasis’, oftewel ‘geaccepteerd samenvallen van longdelen’. In deze nieuwe strategie worden patiënten beademend met relatief lage PEEP niveaus zonder rekruteer manoeuvres, wat waarschijnlijk overrekking van longblaasjes vermindert. ‘Permissive atelectasis’ kan echter wel leiden tot lage zuurstoffracties en een lage zuurstofsaturatie in het bloed. Dit kan eventueel worden opgevangen door het percentage ingeademde zuurstof licht te verhogen.
In hoofdstuk 4 en 5 presenteren wij een internationale prospectieve observationele studie, gericht op het in kaart brengen van de huidige intra-operatieve beademingsstrategieën en op het onderzoeken de relatie tussen verschillende beademingsinstellingen en het optreden van postoperatieve pulmonale complicaties.38, Onze hypothese was dat lage teugvolumes en hogere PEEP niveaus het meest toegepast worden, en dat beiden een associatie hebben met een verminderde incidentie van postoperatieve pulmonale complicaties. Gedurende een periode van zeven dagen werd in 146 centra wereldwijd data verzameld van 8,327 volwassen chirurgische patiënten die mechanische beademing tijdens algehele anesthesie ondergingen. Intra-operatieve beademingsinstellingen werden verzameld en postoperatieve pulmonale complicaties gedurende de eerste 5 postoperatieve dagen werden geregistreerd. Onze resultaten laten zien dat patiënten over het algemeen worden beademd met relatief lage teugvolumes (mediaan van
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500.0 [454.2 – 550.5] mL of 8.1 [7.2 – 9.1] mL/kg PBW), een PEEP niveau van 4.0 [0.0 – 5.0] cmH2O en dat rekruteer manoeuvres zelden worden toegepast (9.5%). De maat van de gekozen teugvolumes lijkt sterk op de standard instellingen van veel beademingsmachines (500 mL), wat doet vermoeden dat de beademingsinstellingen weinig op het individu worden aangepast. Postoperatieve pulmonale complicaties kwamen vaak voor (10.4%) en waren geassocieerd met langere ziekenhuisopname en hogere ziekenhuismortaliteit. Twee methodologisch verschillende multivariate analyses lieten beiden zien dat hogere PEEP niveaus geassocieerd waren met het ontwikkelen van postoperatieve pulmonale complicaties, terwijl dit niet gold voor grotere teugvolumes.
In hoofdstuk 6 beschrijven wij de resultaten van een meta-analyse van individuele patiëntdata van 15 gerandomiseerde studies naar intra-operatieve long-beschermende beademing.39 Onze hypothese was dat intra-operatieve beademing met lage teugvolumes beschermt tegen het ontwikkelen van postoperatieve pulmonale complicaties en het klinisch beloop (duur van opname en ziekenhuissterfte) verbetert. Verder was onze hypothese dat het gebruik van hogere PEEP niveaus bijdraagt aan het beschermende effect van lage teugvolumes. De resultaten (verkregen bij totaal 2,127 patiënten) lieten zien dat intra-operatieve long-beschermende beademing de incidentie van postoperatieve pulmonale complicaties vermindert, maar dat het geen effect heeft op het verdere postoperatieve beloop. Patiënten die een pulmonale complicatie ontwikkelden in de postoperatieve periode hadden wel een verlengde duur van opname op de Intensive Care en in het ziekenhuis, alsmede een verhoogde mortaliteit. De analyse van het individuele effect van lage teugvolumes, liet een verminderde incidentie van postoperatieve pulmonale complicaties zien. Wanneer het gebruik van hogere PEEP niveaus werd toegevoegd aan de analyse van lage teugvolumes, nam het beschermende effect niet toe. In de analyse van het individuele effect van hogere PEEP niveaus werd geen significant effect op het ontwikkelen van postoperatieve pulmonale complicaties gezien.
In hoofdstukken 7 en 8 beschrijven wij een internationale studies waarin beademing met PEEP niveaus van 12 cmH2O gecombineerd met rekruteer manoeuvres worden vergeleken met PEEP niveaus van 2 cmH2O zonder rekruteer manoeuvres tijdens beademing met lage teugvolumes in niet-obese patiënten met een verhoogd risico op het ontwikkelen van postoperatieve pulmonale complicaties die open buik chirurgie ondergaan.40, 41 In deze studie hebben wij de hypothese getest of beademing met hogere PEEP niveaus met rekruteer manoeuvres beschermt tegen het ontwikkelen van postoperatieve pulmonale complicaties. Wij hebben 900 patiënten uit 30 centra verspreid over Europa en Noord- en Zuid-Amerika geïncludeerd. De incidentie van pulmonale complicaties gedurende de eerste 5 postoperatieve dagen verschilde niet tussen patiënten die hogere PEEP niveaus ontvingen en patiënten die met lage PEEP niveaus werden beademend. Patiënten beademd met hogere PEEP niveaus ontwikkelden vaker lage bloeddrukken tijdens de operatie en hadden vaker medicatie nodig om de bloeddruk te verhogen. Patiënten beademd met lage PEEP niveaus hadden intra-operatief vaker een lage zuurstofsaturatie. De resultaten van deze trial suggereren dat long-beschermende beademing met lage teugvolumes niet verder verbeterd wordt door het toepassen van hogere PEEP niveaus met rekruteer manoeuvres tijdens intra-operatieve beademing en dat hogere PEEP niveaus mogelijk kunnen leiden tot een verslechterde hemodynamiek. In hoofdstuk 9 presenteren wij enkele commentaren op dit stuk, samen met onze reactie hierop.42
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In de studie gerapporteerd in hoofdstuk 10 hebben wij onderzocht of het ontwikkelen van postoperatieve longschade bijdraagt aan sterfte. Wij hebben een tweede meta-analyse gedaan waarbij we individuele patiëntdata uit 12 verschillende onderzoeken naar intra-operatieve beschermende beademing hebben gebruikt.43 Onze hypothese was dat het ontwikkelen van postoperatieve longschade geassocieerd is met een slechtere uitkomst en dat de intra-operatieve beademingsinstellingen effect hebben op het postoperatieve beloop. In een cohort van 3365 patiënten bleek het ontwikkelen van postoperatieve longschade geassocieerd te zijn met een verhoogde mortaliteit, met name bij patiënten die geopereerd werden in de borstkas (thoracale procedure), vergeleken met patiënten die buikchirurgie ondergingen. Het ontwikkelen van postoperatieve longschade kwam tussen deze twee groepen overeen. Het ontstaan van longschade was geassocieerd met een langere opnameduur op de Intensive Care en in het ziekenhuis. Het gebruik van beschermende beademingsstrategieën was geassocieerd met een lagere incidentie van postoperatieve longschade, maar het had geen effect op het klinisch beloop. Wanneer een patiënt postoperatief longschade ontwikkelde bleek de voorafgaande intra-operatieve beademing geen invloed te hebben op het wel of niet overlijden van de patiënt. Dit suggereert dat de positieve invloed van intra-operatieve long-beschermende beademing beperkt is tot het verminderen van postoperatieve longschade en geen invloed heeft op mortaliteit.
In hoofdstuk 11 beschrijven wij hoe we ons onderzoek uitbreidden van de operatiekamers naar patiënten die postoperatief beademd worden op de Intensive Care. Hiervoor analyseerden wij data van twee eerdere studies naar patiënten die een geplande ongecompliceerde coronaire bypass operatie ondergingen.44, 45 Wij onderzochten of beademen met hogere PEEP niveaus tijdens de postoperatieve periode effect had op de compliantie van het respiratoire systeem en op gasuitwisseling in de long tijdens de eerste uren postoperatieve beademing. Met de compliantie van het respiratoire systeem wordt de verandering van longvolume bij een bepaalde beademingsdruk bedoeld, dit komt overeen met de elastische krachten van de long. Verder onderzochten wij of beademen met hogere PEEP niveaus invloed had op de totale duur van postoperatieve beademing.46 Wij testten de hypothese dat hogere PEEP niveaus resulteren in betere compliantie en gaswisseling, maar geen invloed hebben op duur van postoperatieve beademing. In een cohort van 121 patiënten stelden wij vast dat hogere PEEP niveaus leidden tot betere compliantie en gaswisseling, maar dat dit effect alleen bleef bestaan bij PEEP niveaus boven 5 cmH2O. Na verwijderen van de beademingsbuis verdwenen de verbeterde compliantie en gaswisseling. Patiënten die beademend werden met hogere PEEP niveaus hadden minder extra zuurstoftoediening nodig op de afdeling waar ze verder herstelden van hun operatie, wat suggereert dat zij mogelijk minder vorming van atelectase hadden. De totale duur van de postoperatieve beademing was langer in patiënten beademd met hogere PEEP niveaus. Een gedeeltelijke verklaring hiervoor zou kunnen zijn dat deze patiënten meer en langer slaapmiddelen kregen toegediend.
Discussie
De belangrijkste bevinding van dit proefschrift is dat intra-operatieve beademing met hogere PEEP niveaus in patiënten met een normaal gewicht die een grote chirurgische ingreep ondergaan niet lijkt te beschermen tegen het ontwikkelen van postoperatieve pulmonale complicaties
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tijdens beademing met lage teugvolumes (hoofdstuk 6 en 8). Hogere PEEP niveaus kunnen zelfs potentieel schade veroorzaken, door verslechtering van de hemodynamiek (hoofdstuk 8) en mogelijk ook door toename van het risico op postoperatieve pulmonale complicaties (hoofdstuk 5).
In dit proefschrift laten wij verder zien dat long-protectieve beademing met lage teugen en hogere PEEP niveaus beschermt tegen het ontwikkelen van postoperatieve pulmonale complicaties, maar dat dit geen invloed heeft op duur van opname of mortaliteit (hoofdstukken 6 en 10). Patiënten die postoperatief een pulmonale complicatie ontwikkelen hebben wel een langere opnameduur en een hogere mortaliteit (hoofdstukken 5, 6 en 10). Tot slot, bij patiënten die een cardiale bypass operatie ondergingen verbetert het toedienen van hogere PEEP niveaus tijdens postoperatieve beademing de compliantie en oxygenatie, maar dit houdt geen stand na het stoppen van de beademing en het verwijderen van de beademingsbuis. De duur tussen het einde van de operatie en extubatie was in deze groep verlengd (hoofdstuk 11).
PEEP beschermt mogelijk nietIn tegenstelling tot ‘de algemene opvatting’, laat dit proefschrift zien dat beademing met hogere PEEP niveaus niet bijdraagt aan het beschermende effect van beademing met lage teugen op het ontwikkelen van postoperatieve pulmonale complicaties. Een meta-analyse van individuele patiëntdata liet zien dat er geen toegevoegd beschermend effect van hogere PEEP niveaus is op de incidentie van pulmonale complicaties in patiënten die beademend werden met lage teugvolumes (hoofdstuk 6).39 Dezelfde studie vond geen directe associatie tussen het niveau van PEEP en het ontwikkelen van postoperatieve pulmonale complicaties. Bij patiënten na een cardiale bypass operatie bleek beademing met hogere PEEP niveaus geen blijvend effect te hebben op longcompliantie of verbeterde gaswisseling (hoofdstuk 11).46 Uit de PROVHILO trial bleek dat beademing met PEEP van 12 cmH2O niet beschermde tegen het ontwikkelen van postoperatieve complicaties tijdens beademing met lage teugen (hoofdstuk 8).41 Het niveau van PEEP dat gebruikt werd in deze studie werd bekritiseerd, omdat het hoger is dan het niveau van PEEP dat over het algemeen wordt toegepast in de klinische praktijk.47 De hogere PEEP drukken zouden de drukken aan het eind van de inspiratie hebben verhoogd, wat mogelijk de longblaasjes heeft kunnen overrekken. Dit zou het beschermende effect van hogere niveaus van PEEP teniet kunnen hebben gedaan. Wij hebben echter het niveau van PEEP gebaseerd op eerdere experimenten, waar een PEEP niveau boven de 10 cmH2O werd aangeraden om het repetitief openen en sluiten van de longblaasjes tijdens intra-operatieve beademing te voorkomen.48-50 Zoals wij bespreken in onze ‘Author’s reply’ (hoofdstuk 9),42 hebben wij in onze studie geobserveerd dat de hogere PEEP groep een toename van compliantie had tijdens intra-operatieve beademing. Dit suggereert dat de longblaasjes effectief worden geopend tijdens de beademing, zonder duidelijke tekenen van overrekking. Aan de andere kant zagen wij ook dat de hogere PEEP groep hogere drukken aan het einde van de inademing had (zogenaamde peak drukken), wat bijgedragen zou kunnen hebben aan overrekking van delen van de long.
PEEP kan mogelijk schade veroorzakenHet gebruik van hogere PEEP niveaus zou zelfs mogelijk schade kunnen veroorzaken. Hogere PEEP niveaus verslechteren de intra-operatieve hemodynamiek (hoofdstuk 8)41 en kunnen zelfs het risico op postoperatieve pulmonale complicaties verhogen (hoofdstuk 5). Bij beademde
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patiënten na cardiale bypass chirurgie lijken hogere PEEP niveaus de totale postoperatieve beademingsduur te verlengen (hoofdstuk 11).46
Het nadelige effect van PEEP op de hemodynamiek is eerder beschreven.51, 52 De negatieve effecten van PEEP op het ontwikkelen van postoperatieve pulmonale complicaties is echter in strijd met eerdere recente studies.27, 53, 54 Een mogelijke verklaring hiervoor is, dat vergeleken met deze trials, de toegediende teugvolumes veel kleiner waren. In de LAS VEGAS studie vonden wij ook geen verband tussen de grootte van teugvolumes en het ontwikkelen van postoperatieve complicaties. Wanneer beademd wordt met lage teugvolumes, zouden te hoge PEEP niveaus mogelijk kunnen bijdragen aan het overrekken van bepaalde longdelen.
Driving pressureExperimentele studies laten inderdaad zien dat beademing met te hoge drukken aan het einde van de inademing (plateau drukken) schadelijk is voor de long (‘stress’). Echter, mogelijk is de repetitieve uitrekking van longblaasjes gedurende de ademcyclus (‘strain’) meer schadelijk.55-58 De maximale uitrekking van de long tijdens beademing kan het beste worden berekend door de ‘driving pressure’: de drukken bij het einde van de inademing (plateau drukken) minus de positieve drukken bij het einde van de uitademing (PEEP).
In beademde ratten lijkt driving pressure de belangrijkste schadelijke factor van beademing.59 In studies bij patiënten met ARDS lijkt er een associatie te bestaan tussen driving pressure en slechtere klinische uitkomst.60-62 In een grote individuele patiëntdata analyse van klinische studies die het effect van beschermende beademing onderzochten in patiënten met ARDS, bleek driving pressure van alle beademingsfactoren het sterkst geassocieerd met mortaliteit.63
PEEP en driving pressure De effecten van PEEP op het open houden van de long versus het overrekken van de long is complex. Aan de ene kant kan PEEP voorkomen dat longdelen samenvallen, waardoor de long homogeen open blijft en het repetitieve samenvallen van longdelen aan het einde van de uitademing wordt voorkomen. Aan de andere kant, wanneer het niveau van PEEP niet effectief de long open houdt, stijgen de drukken aan het einde van de inademing, wat kan leiden tot overrekking van longblaasjes en tot schade aan de long.56, 64, 65 Het optimum binnen dit delicate balans blijft onduidelijk en verschilt mogelijk per patiënt.
Wellicht kan PEEP in de toekomst per patiënt ingesteld worden, zodat de optimale driving pressure (plateau drukken min PEEP) kan worden gevonden per patiënt en zo longschade kan worden verminderd.
Meer onderzoek zal moeten worden verricht naar de effecten van driving pressure op postoperatieve complicaties en hoe driving pressure (en dus PEEP) het beste kan worden ingesteld op de beademingsmachine.
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Conclusie
Dit proefschrift toont als eerste aan dat intra-operatieve beademing met hogere PEEP niveaus in patiënten met een normaal gewicht die een grote chirurgische ingreep ondergaan niet lijkt te beschermen tegen het ontwikkelen van postoperatieve pulmonale complicaties tijdens beademing met lage teugvolumes. Hogere PEEP niveaus kunnen zelfs mogelijk schade veroorzaken door verslechtering van de intra-operatieve hemodynamiek en toename van het risico op postoperatieve pulmonale complicaties.
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41. Hemmes SN, Gama de Abreu M, Pelosi P, Schultz MJ. High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial. Lancet 2014; 384(9942): 495-503
42. Hemmes SN, de Abreu MG, Pelosi P, Schultz MJ. Positive end-expiratory pressure during surgery - Authors’ reply. Lancet 2014; 384(9955): 1670-1
43. Serpa Neto A, Hemmes SN, Barbas CS, et al. Incidence of mortality and morbidity related to postoperative lung injury in patients who have undergone abdominal or thoracic surgery: a systematic review and metaanalysis. The Lancet Respiratory medicine 2014; 2(12): 1007-15
44. Dongelmans DA, Veelo DP, Paulus F, et al. Weaning automation with adaptive support ventilation: a randomized controlled trial in cardiothoracic surgery patients. Anesthesia and analgesia 2009; 108(2): 565-71
45. Dongelmans DA, Veelo DP, Binnekade JM, et al. Adaptive support ventilation with protocolized de-escalation and escalation does not accelerate tracheal extubation of patients after nonfast-track cardiothoracic surgery. Anesthesia and analgesia 2010; 111(4): 961-7
46. Dongelmans DA, Hemmes SN, Kudoga AC, Veelo DP, Binnekade JM, Schultz MJ. Positive end-expiratory pressure following coronary artery bypass grafting. Minerva anestesiologica 2012; 78(7): 790-800
47. Futier E. Positive end-expiratory pressure in surgery: good or bad? Lancet 2014; 384(9942): 472-448. Brismar B, Hedenstierna G, Lundquist H, Strandberg A, Svensson L, Tokics L. Pulmonary densities during anesthesia
with muscular relaxation--a proposal of atelectasis. Anesthesiology 1985; 62(4): 422-849. Hachenberg T, Lundquist H, Tokics L, Brismar B, Hedenstierna G. Analysis of lung density by computed tomography
before and during general anaesthesia. Acta anaesthesiologica Scandinavica 1993; 37(6): 549-55
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50. Neumann P, Rothen HU, Berglund JE, Valtysson J, Magnusson A, Hedenstierna G. Positive end-expiratory pressure prevents atelectasis during general anaesthesia even in the presence of a high inspired oxygen concentration. Acta anaesthesiologica Scandinavica 1999; 43(3): 295-301
51. Nielsen J, Ostergaard M, Kjaergaard J, et al. Lung recruitment maneuver depresses central hemodynamics in patients following cardiac surgery. Intensive care medicine 2005; 31(9): 1189-94
52. Luecke T, Pelosi P. Clinical review: Positive end-expiratory pressure and cardiac output. Critical Care 2005; 9(6): 607-2153. Ge Y, Yuan L, Jiang X, Wang X, Xu R, Ma W. [Effect of lung protection mechanical ventilation on respiratory function in
the elderly undergoing spinal fusion]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2013; 38(1): 81-554. Severgnini P, Selmo G, Lanza C, et al. Protective mechanical ventilation during general anesthesia for open abdominal
surgery improves postoperative pulmonary function. Anesthesiology 2013; 118(6): 1307-2155. Wakabayashi K, Wilson MR, Tatham KC, O’Dea KP, Takata M. Volutrauma, but not atelectrauma, induces systemic
cytokine production by lung-marginated monocytes. Critical care medicine 2014; 42(1): e49-5756. Caironi P, Langer T, Carlesso E, Protti A, Gattinoni L. Time to generate ventilator-induced lung injury among mammals
with healthy lungs: a unifying hypothesis. Intensive care medicine 2011; 37(12): 1913-2057. Tschumperlin DJ, Oswari J, Margulies AS. Deformation-induced injury of alveolar epithelial cells. Effect of frequency,
duration, and amplitude. American journal of respiratory and critical care medicine 2000; 162(2 Pt 1): 357-6258. Garcia CS, Rocco PR, Facchinetti LD, et al. What increases type III procollagen mRNA levels in lung tissue: stress induced
by changes in force or amplitude? Respiratory physiology & neurobiology 2004; 144(1): 59-7059. Dreyfuss D, Saumon G. Role of tidal volume, FRC, and end-inspiratory volume in the development of pulmonary edema
following mechanical ventilation. The American review of respiratory disease 1993; 148(5): 1194-20360. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory
distress syndrome. The New England journal of medicine 1998; 338(6): 347-5461. Estenssoro E, Dubin A, Laffaire E, et al. Incidence, clinical course, and outcome in 217 patients with acute respiratory
distress syndrome. Critical care medicine 2002; 30(11): 2450-662. Boissier F, Katsahian S, Razazi K, et al. Prevalence and prognosis of cor pulmonale during protective ventilation for
acute respiratory distress syndrome. Intensive care medicine 2013; 39(10): 1725-3363. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. The
New England journal of medicine 2015; 372(8): 747-5564. Protti A, Votta E, Gattinoni L. Which is the most important strain in the pathogenesis of ventilator-induced lung injury:
dynamic or static? Current opinion in critical care 2014; 20(1): 33-865. Gattinoni L, Carlesso E, Caironi P. Stress and strain within the lung. Current opinion in critical care 2012; 18(1): 42-7
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Nederlandse samenvatting
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Contributing authors and affiliations
C.S. BarbasDepartment of Pneumology, Heart Institute (INCOR), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilDepartment of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil
M. BeiderlindenDepartment of Anaesthesiology, Düsseldorf University Hospital, Düsseldorf, GermanyDepartment of Anaesthesiology, Marienhospital Osnabrück, Osnabrück, Germany
M. BiehlDivision of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
J.M. BinnekadeDepartment of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
J. CanetDepartment of Anesthesiology, Hospital Universitar I Germans Trias I Pujol, Barcelona, Spain
D.A. DongelmansDepartment of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
A. Fernandez-BustamanteDepartment of Anesthesiology, University of Colorado, Aurora, Colorado, USA
E. FutierDepartment of Anesthesiology and Critical Care Medicine, Estaing University Hospital, Clermont-Ferrand, France
O. GajicDivision of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
M. Gama de AbreuDepartment of Anesthesiology and Intensive Care Medicine, Pulmonary Engineering Group, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
A. Güldner Department of Anesthesiology and Intensive Care Medicine, Pulmonary Engineering Group, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
G. HedenstiernaDepartment of Medical Sciences, Section of Clinical Physiology, University Hospital, Uppsala, Sweden
297
Authors and affiliations
M. HiesmayrDivision Cardiac-, Thoracic-, Vascular Anesthesia and Intensive Care, Medical University, Vienna, Austria
M.W. HollmannDepartment of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsLaboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
S. Jaber Department of Critical Care Medicine and Anesthesiology (SAR B), Saint Eloi University Hospital, Montpellier, France
T. Kiss Department of Anesthesiology and Intensive Care Medicine, Pulmonary Engineering Group, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
A. KozianDepartment of Anesthesiology and Intensive Care Medicine, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
A.C. Kudoga Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
M. LickerDepartment of Anaesthesiology, Pharmacology and Intensive Care, Faculty of Medicine, University Hospital of Geneva, Geneva, Switzerland.
W.Q. LinState Key Laboratory of Oncology of South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China
A.D. MaslowDepartment of Anesthesiology, The Warren Alpert School of Brown University, Providence, Rhode Island
S.G. MemtsoudisDepartment of Anesthesiology, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York, USA
P. MoineDepartment of Anesthesiology, University of Colorado, Aurora, Colorado, USA
298
T. NgDepartment of Surgery, The Warren Alpert School of Brown University, Providence, Rhode Island
D. PaparellaDepartment of Emergency and Organ Transplant (D.E.T.O.), Division of Cardiac Surgery, University of Bari Aldo Moro, Bari, Italy
P. PelosiDepartment of Surgical Sciences and Integrated Diagnostics, IRCCS San Martino IST, University of Genoa, Genoa, Italy
C. PutensenDepartment of Anesthesiology, University of Bonn, Bonn, Germany
M. RanieriAnestesiologia e Rianimazione, Dipartimento di Discipline Medico-Chirurgiche, Università di Torino, Turin, Italy
D. Reis MirandaDepartment of Intensive Care, Erasmus MC, Rotterdam, The Netherlands
P.R. RoccoLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
F. ScavonettoDepartment of Anesthesiology and Anesthesia Clinical Research Unit, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
T. SchillingDepartment of Anesthesiology and Intensive Care Medicine, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
W. SchmidDepartment of Cardiothoracic and Vascular Anesthesia and Intensive Care, Medical University, Vienna, Austria
M.J. SchultzDepartment of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsLaboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
G. SelmoDepartment of Environment, Health and Safety, University of Insubria, Varese, Italy
299
Authors and affiliations
A. Serpa NetoDepartment of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsDepartment of Pneumology, Heart Institute (INCOR), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilDepartment of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil
P. Severgnini Department of Environment, Health and Safety, University of Insubria, Varese, Italy
P. SpiethDepartment of Anesthesiology and Intensive Care Medicine, Pulmonary Engineering Group, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
J. Sprung Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
S. SundarDepartment of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
D. TalmorDepartment of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
T. TreschanDepartment of Anaesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany
E.M. TschernkoDivision Cardiac-, Thoracic-, Vascular Anesthesia and Intensive Care, Medical University, Vienna, Austria
C. UnzuetaDepartment of Anaesthesiology, Hospital de Sant Pau, Barcelona, Spain
D.P. Veelo Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsLaboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
T.N. WeingartenDepartment of Anesthesiology and Anesthesia Clinical Research Unit, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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E.K. WolthuisDepartment of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsLaboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
H. WriggeDepartment Anesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany
301
Authors and affiliations
302
Publications SNT Hemmes
Güldner A, Kiss T, Serpa Neto A, Hemmes SN, Canet J, Spieth PM, Rocco PR, Schultz MJ, Pelosi P, de Abreu MG.Intraoperative Protective Mechanical Ventilation for Prevention of Postoperative Pulmonary Complications: A Comprehensive Review of the Role of Tidal Volume, Positive End-expiratory Pressure, and Lung Recruitment Maneuvers.Anesthesiology 2015; 122(3): 631-46
Serpa Neto A, Hemmes SN, Barbas CS, Beiderlinden M, Biehl M, Binnekade JM, Canet J, Fernandez-Bustamante A, Futier E, Gajic O, Hedenstierna G, Hollmann MW, Jaber S, Kozian A, Licker M, Lin WQ, Maslow AD, Memtsoudis SG, Reis Miranda D, Moine P, Ng T, Paparella D, Putensen C, Ranieri M, Scavonetto F, Schilling T, Schmid W, Selmo G, Severgnini P, Sprung J, Sundar S, Talmor D, Treschan T, Unzueta C, Weingarten TN, Wolthuis EK, Wrigge H, Gama de Abreu M, Pelosi P, Schultz MJ.Protective versus Conventional Ventilation for Surgery: A Systematic Review and Individual Patient Data Metaanalysis.Anesthesiology 2015; May 15 [ePub ahead of print]
Serpa Neto A, Hemmes SN, Barbas CS, Beiderlinden M, Fernandez-Bustamante A, Futier E, Hollmann MW, Jaber S, Kozian A, Licker M, Lin WQ, Moine P, Scavonetto F, Schilling T, Selmo G, Severgnini P, Sprung J, Treschan T, Unzueta C, Weingarten TN, Wolthuis EK, Wrigge H, Gama de Abreu M, Pelosi P, Schultz MJ; PROVE Network investigators.Incidence of mortality and morbidity related to postoperative lung injury in patients who have undergone abdominal or thoracic surgery: a systematic review and metaanalysis.Lancet Respir Med 2014;2(12):1007-15
Hemmes SN, de Abreu MG, Pelosi P, Schultz MJ.Positive end-expiratory pressure during surgery - Authors’ reply.Lancet 2014;8;384(9955):1670-1
PROVE Network Investigators for the Clinical Trial Network of the European Society of Anaesthesiology, Hemmes SN, Gama de Abreu M, Pelosi P, Schultz MJ.High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial.Lancet 2014;9;384(9942):495-503
Bakker OG, Hemmes SN, Backes Y, Determann RM, Schultz MJ.SuPAR in pleural fluid may function as a biological marker for infection in critically ill patients with pleural effusions.J Infect 2014;68(6):607-9
Serpa Neto A, Hemmes SN, de Abreu MG, Pelosi P, Schultz MJ; PROVE Network investigators.Protocol for a systematic review and individual patient data metaanalysis of benefit of so-called lung-protective ventilation settings in patients under general anesthesia for surgery.Syst Rev 2014;2;3:2
303
Publications
Hegeman MA, Hemmes SN, Kuipers MT, Bos LD, Jongsma G, Roelofs JJ, van der Sluijs KF, Juffermans NP, Vroom MB, Schultz MJ.The extent of ventilator-induced lung injury in mice partly depends on duration of mechanical ventilation.Crit Care Res Pract;2013:435236
Hemmes SN, Paulus F, Schultz MJ.From the dark side of ventilation toward a brighter look at lungs.Crit Care Med 2013;41(5):1376-7
Hemmes SN, de Abreu MG, Pelosi P, Schultz MJ.ESA Clinical Trials Network 2012: LAS VEGAS--Local Assessment of Ventilatory Management during General Anaesthesia for Surgery and its effects on Postoperative Pulmonary Complications: a prospective, observational, international, multicentre cohort study.Eur J Anaesthesiol 2013;30(5):205-7
Hemmes SN, Serpa Neto A, Schultz MJ.Intraoperative ventilatory strategies to prevent postoperative pulmonary complications: a metaanalysis.Curr Opin Anaesthesiol;2013;26(2):126-33.
Hemmes SN, Severgnini P, Jaber S, Canet J, Wrigge H, Hiesmayr M, Tschernko EM, Hollmann MW, Binnekade JM, Hedenstierna G, Putensen C, de Abreu MG, Pelosi P, Schultz MJ.Rationale and study design of PROVHILO - a worldwide multicenter randomized controlled trial on protective ventilation during general anesthesia for open abdominal surgery.Trials 2011;6;12:111
Submitted manuscriptsHemmes SN, Gama de Abreu M, Pelosi P, Schultz MJ for the The LAS VEGAS Investigators for PROVE Network*, and the Clinical Trial Network of the European Society of AnaesthesiologyIntraoperative Ventilation Strategies and Patient Outcomes Following Surgery: an International Observational Study (LAS VEGAS).*PROVE Network: the PROtective VEntilation Network
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PhD Portfolio
PhD student: S.N.T. HemmesSupervisors: Prof. dr. M.J. Schultz and prof. dr. dr. M.W. HollmannPhD period: September 2010 – December 2015
Entrepreneurship in Health and Life Sciences 2012 0.4
Presentations
Study design of the PROVHILO trial - Protective Ventilation using High versus Low PEEP. Oral presentation and meeting at Euroanesthesia 2011 0.3
Do Soluble Mediators Released In The Airways During Mechanical Ventilation Cause Ventilator-Induced Lung Injury? Poster at the American Thoracic Society International Conference
2012 0.5
Effects of manual hyperinflation on lung aeration in direct and indirect ARDS. Poster at the Annual Congress of the European Society of Intensive Care Medicine
2013 0.5
Study design and first results of (LAS VEGAS) Local ASsessment of VEntilatory Management During General Anesthesia for Surgery and effects on Postoperative Pulmonary Complications: a Prospective Observational International Multi–center Cohort Study. Oral presentation and meeting at Euroanesthesia
2014 0.3
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PhD Portfolio
International conferences
Euroanesthesia 2011 0.75
American Thoracic Society International Conference 2012 1.0
Euroanesthesia 2012 0.75
Annual Congress of the European Society of Intensive Care Medicine 2012 0.75
Euroanesthesia 2013 0.75
Annual Congress of the European Society of Intensive Care Medicine 2013 0.75
Euroanesthesia 2014 0.75
Euroanesthesia 2015 0.75
Other activities
Intensive Care Journal Club (monthly) 2010 - 2013 3
Intensive Care research meeting (weekly) 2010 – 2013 13.5
Laboratory of Experimental Intensive Care and Anesthesiology (LEICA) research meeting (weekly) 2010 – 2013 13.5
Research Internship, Medicine, University of Amsterdam 2012 1.0
Research Internship, Medicine, University of Amsterdam 2012 1.0
Bachelor thesis, Medicine, University of Amsterdam 2012 1.0
Research Internship, Medicine, University of Amsterdam 2013 1.0
Lecturing
306
Can intra-operative mechanical ventilation harm our patients? Oral presentation at the Laboratory of Experimental Intensive Care and Anesthesiology (LEICA) symposium
2013 0.5
Met welk Tidal Volume moeten we ventileren? Yearly training course of Anesthesiologists and Intensivists from The Netheralnds and Belgium. CEEA Course, Antwerpen
Mar&Okt2015 2
High levels of PEEP – Tipping the balance? Oral presentation at AMC symposium, The Update on Intraoperative Ventilation Dec 2015 0.5
Parameters of esteem
Grants
European Society of Anesthesiology Research Grant for PROVHILO trial 2011
European Society of Anesthesiology Clinical Trial Network Grant for LAS VEGAS trial 2012
Awards
ATS International Trainee Travel Award 2012
Ritsema van Eck award, Nederlandse Vereniging van Anesthesiologie, 1st place 2015
DRÄGER Prize in Anaesthesia and Intensive Care Medicine 2015
AMC PhD Publication 2014 Award, 2nd place 2015
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PhD Portfolio
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Curriculum Vitae
Sabrine Hemmes was born on 23 March 1982 in Hilversum, where she spent the first 5 years of her life. After a 3-year period in Atlanta, U.S.A. with her parents, sister and brother, the family came back to Blaricum in 1990. Ten years later, Sabrine graduated from high-school at the Gemeentelijk Gymnasium in Hilversum. Afterwards she spent a year abroad, learning the Spanish language and offering volunteer work to burn-patients in Peru. In this gap-year, Sabrine decided to study Medicine. During her travels through South-America she participated in the ‘decentrale selectie’ of the AMC in Amsterdam with success. In 2011 she commenced with her Medical studies at the Academic Medical Center, University of Amsterdam. During her studies she had a special interest in Tropical Medicine. She completed a summer school in infectious diseases in Egypt and performed her first scientific research on malaria in Malawi. After obtaining her doctors degree in 2008 she left for Uganda to work as a doctor in rural settings for several months. She gained further medical experience at the Surgical Department of the Slotervaartziekenhuis in Amsterdam and the Intensive Care of the Rijnland Ziekenhuis in Leiderdorp. In 2010 she applied to and was accepted for the specialization in Anaesthesiology at the AMC. Meanwhile, Sabrine had become acquainted with prof. dr. Marcus J. Schultz (intensivist), who supervised the work presented in this thesis together with prof. dr. dr. Markus W. Hollmann (anaesthesiologist). In 2013 Sabrine started her traineeship as anaesthesiologist, which she will complete in 2018. She will perform part of her residency in Intensive Care in 2016 in Melbourne, Australia. Next to her clinical activities, Sabrine is still actively involved in several running research projects related to her PhD projects.
309
Curriculum Vitae
310
Acknowledgements
On the road to my doctorate, countless people have helped me and played an essential role. I would like to thank them all, and some in particular.
First of all, the patients who selflessly participated in the several trials and studies. Secondly, all collaborating investigators for their hard work and efforts.Thirdly, all anaesthetic, surgical, out-patient clinic and ward staff, who gave us the opportunity to perform our clinical studies.
I am thankful to my promotores prof. Marcus Schultz and prof. Markus Hollmann:Marcus, for believing in me scientifically, by giving me the opportunity to start on this PhD project. Initiating an international multicentre trial was a new bold adventure for the both of us, which turned out to be a great success and a starting-point for many other international projects.Markus, for believing in me clinically, by giving me time off from clinical duties to focus on my research. Furthermore thank you for your scientific and emotional support; I always had the feeling that you ‘had my back’.
I would like to thank the other members of my doctorate committee for reviewing my thesis and attending my doctoral defence: prof. dr. L.P.H.J. Aarts, prof. dr. C. Boer, prof. dr. M.A. Boermeester, prof. dr. G. Cinnella, prof. dr. M.M. Levi, prof. dr. W.S. Schlack en prof. dr. M.B. Vroom.
Many thanks and warmest wishes to the two professors and one professor-to-be with whom I have collaborated so closely together with Marcus, and with whom I have shared literally thousands of emails: prof. Paolo Pelosi, prof. Marcelo Gama de Abreu and dr. Ary Serpa Neto. The amount of passion and work that you all put into your many simultaneously running studies and into PROVEnet is mindboggling and inspiring.
The European Society of Anaesthesiology for generously supporting several of our studies and for believing in our ideas. In specific Brigitte, Sandrine and Benoit for their endless efforts and support in the execution of PROVHILO and LAS VEGAS. It has been a tremendous job and a great achievement! We could (really!) not have done it without you. Above all it was a great pleasure to work with you.
Mijn kamergenoten gedurende mijn eerste 3 promotiejaren: Luuk en Lieuwe. Jullie waren mijn wetenschappelijk brein, klankbord en geweten. Zonder jullie had ik dit dankwoord nu niet geschreven. Luuk, veel dank voor jouw eindeloos geduld, luisterend oor en diplomatieke adviezen. Niet alleen op wetenschappelijk vlak, maar ook op het gebied van huizenkoperij, belasting en persoonlijk vlak.Lieuwe, ik had graag gewild dat jij mijn co-promotor had kunnen zijn. Ik heb het geprobeerd! Je hebt het zeker verdiend; ik heb zoveel met jou gebrainstormd over mijn onderzoeken en over beademing in het algemeen. Het stelde mij altijd gerust, dat -mocht ik onder een tram komen- jij feilloos al mijn onderzoek zou kunnen overnemen (gelukkig had jij ook al mijn wachtwoorden). Jullie waren mijn belangrijkste steunpilaren binnen mijn promotie. Balen dat jullie beiden niet aan mijn zijde kunnen staan op ‘le moment suprême’.
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Acknowledgements
Aline, jij hoort hier eigenlijk ook bij. We hebben veel te kort van je vrolijkheid en wijsheid mogen genieten; jij maakte onze drie-eenheid tot een evenwichtig kwartet.
Thanks to all my other co-PhD’s from the Intensive Care and LEICA: Roos, Marleen, Charlotte, Friso, Hamid, Ilse, Daniel, Djai, Gezina, Robert, Lonneke, Maryse, Esther, Laura, Gerie, Rianne, Frank, Hendrik en Hemmik for the great times we have had. I always considered the ICU/LEICA research-group as the greatest PhD-group of the AMC.Furthermore, I would like to thank the other researchers of the ICU: Frederique, Jan, Marjon, Annelou, Tineke, Mark, Nicole, Janneke, Dave, Marcella, Thomas, Wim, Mary-Anne, Erica, and from the LEICA: Anita, Gearstje, Jessica en Koen. Specifically Jan for all the hours of work on the impossible data-exports, Annelou for performing the PROVHILO monitoring abroad, Anita for all her help and gezelligheid in the lab, and Frederique for the great collaboration and the long talks about PhD-life and life outside research.
Many thanks to all my great colleagues, supervisors and nurse anaesthetists from the Anaesthesia Departments of both the AMC and OLVG, and to dr. Peter de Haan in specific. I have learnt so much from all of you the last two years. It has been a great pleasure to work by your side!
Love and thanks to all my fantastic and inspiring friends, who give so much joy and richness to my life. The last two years I’ve seen far to little of you guys… Change is coming!
My dear paranimfs Jet and Pieter Roel; it was an honour for me to be paranimf at both your defences. Now I am very proud to have such brilliant people by my side during my thesis defence. Jet, you are one of the warmest, most supportive people I know. And lucky me; I had you close during my PhD course, as we did our doctoral programmes at the same time in the same hospital! I hope to enjoy your friendship the rest of my life. Pieter Roel, we started off on our PhD in room G3-227, where we shared the same humour and our love for music. You soon left to complete your ICU fellowship, but it has always surprised me that we developed such a great friendship in such a short time. Lots of love to my family, who provided a stable, warm home and for the greatest part made me into the person I am today. They gave me endless support during my PhD project, even though they maybe did not always completely comprehend the mysteries of Medical Science. “Okay, so if I understand correctly... On a scale from Donald Duck to Times Magazine, you just published in the Times!”
